USRE50320E1 - APOE mimetic peptides and higher potency to clear plasma cholesterol - Google Patents

APOE mimetic peptides and higher potency to clear plasma cholesterol Download PDF

Info

Publication number
USRE50320E1
USRE50320E1 US17/748,682 US201517748682A USRE50320E US RE50320 E1 USRE50320 E1 US RE50320E1 US 201517748682 A US201517748682 A US 201517748682A US RE50320 E USRE50320 E US RE50320E
Authority
US
United States
Prior art keywords
seq
peptide
amino
apoe
lrrlrrrllrdwlkafydkvaeklkeaf
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US17/748,682
Inventor
Gattadahalli M. Anantharamaiah
Dennis Goldberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UAB Research Foundation
Anji Pharmaceuticals Inc
Original Assignee
UAB Research Foundation
Anji Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by UAB Research Foundation, Anji Pharmaceuticals Inc filed Critical UAB Research Foundation
Priority to US17/748,682 priority Critical patent/USRE50320E1/en
Assigned to ANJI PHARMACEUTICALS INC. reassignment ANJI PHARMACEUTICALS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LIPIMETIX DEVELOPMENT, INC.
Assigned to UAB RESEARCH FOUNDATION reassignment UAB RESEARCH FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ANANTHARAMAIAH, GATTADAHALLI M.
Assigned to LIPIMETIX DEVELOPMENT, INC. reassignment LIPIMETIX DEVELOPMENT, INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: LIPIMETIX DEVELOPMENT, LLC
Assigned to LIPIMETIX DEVELOPMENT, LLC reassignment LIPIMETIX DEVELOPMENT, LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GOLDBERG, DENNIS
Application granted granted Critical
Publication of USRE50320E1 publication Critical patent/USRE50320E1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/775—Apolipopeptides

Definitions

  • cardiovascular disease In the United States, heart disease is the leading cause of death in both men and women. Several causative factors are implicated in the development of cardiovascular disease including hereditary predisposition to the disease, gender, lifestyle factors such as smoking and diet, age, hypertension, and hyperlipidemia, including hypercholesterolemia. Several of these factors, particularly hyperlipidemia and hypercholesteremia (high blood cholesterol concentrations) provide a significant risk factor associated with atherosclerosis.
  • Atherosclerosis is associated with an inflammatory response caused by the accumulation of low-density lipoprotein (LDL) molecules in blood vessels. It can be asymptomatic for years. Atherosclerosis causes hardening and narrowing of blood vessels. There are several treatments for atherosclerosis, such as lifestyle change, medication and medical procedures. Statins are a well-known treatment for atherosclerosis. Statins have proven to reduce cardiac risk however the withdrawal of statin therapy abrogrates the protective effect (Heeschen et al. Circulation. 105:1446-1452, 2002).
  • the current approach to treating atherosclerosis is to provide earlier intervention and life-long treatment. This approach is problematic as it requires identifying asymptomatic patients early in their life cycle and, since risk increases with age, maintaining therapy for the duration of their life. Further, the most efficacious currently available therapies are unable to prevent major cardiac events in all patients whether as primary or secondary interventions. Therefore, there is a need for therapies that can provide rapid benefit in reducing atherosclerosis and have long-term effects that do not require constant administration.
  • the compositions and methods disclosed herein provide an atherosclerosis therapy with sustained therapeutic effects even after the treatment is withdrawn.
  • ApoE apolipoprotein E
  • ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an acetylated amino hexanoic acid (Ac-Aha).
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the Ac-Aha can be at the N-terminus of the peptide.
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain.
  • the class A amphipathic-helical domain can be DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein said apolipoprotein E is from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein said synthetic peptide is protected using an amide group at the C-terminus.
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of ApoE is LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), or RLTRKRGLK (SEQ ID NO:13).
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of ApoE is LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), RLTRKRGLK (SEQ ID NO:13), LRRMRRRLMR (SEQ ID NO:621), or RLTRRRGK (SEQ ID NO:622).
  • LRKLRKRLLR SEQ ID NO:4
  • LRRLRRRLLR SEQ ID NO:11
  • LRKMRKRLMR SEQ ID NO:7
  • RLTRKRGLK SEQ ID NO:13
  • LRRMRRRLMR SEQ ID NO:621
  • RLTRRRGK SEQ ID NO:622
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH 2 or Ac-Aha-[R]hE18A-NH 2 .
  • the ⁇ -amino fatty acid moiety can be inserted between the lipid-associating peptide and the receptor binding domain of apoE.
  • the class A amphipathic-helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
  • apolipoprotein E can be from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
  • RNA binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), or RLTRKRGLK (SEQ ID NO:13).
  • the receptor binding domain of ApoE can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO:12), LRKLPKRLLR (SEQ ID NO:8), LRNVRKRLVR (SEQ ID NO:9), MRKLRKRVLR (SEQ ID NO:10), LRRLRRRLLR (SEQ ID NO:11), LRKLRKRFFR (SEQ ID NO:12), LRKLRKRLLR (SEQ ID NO:4), or LRKMRKRLMR (SEQ ID NO:7).
  • LRKLRKRLLR SEQ ID NO:4
  • LRRLRRRLLR SEQ ID NO:11
  • LRKMRKRLMR SEQ ID NO:7
  • RLTRKRGLK SEQ ID NO:13
  • LRRMRRRLMR SEQ ID NO:621
  • RLTRRRGK RLTRRRGK
  • RNA molecules comprising a receptor binding domain of ApoE and a lipid-associating peptide
  • the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ⁇ -amino fatty acid moiety, or an acetylated ⁇ -amino fatty acid moiety
  • the synthetic ApoE-mimicking peptide can be: butanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO: 623); hexanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO: 624); octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO: 625); decanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH
  • fatty acid moiety is shown at the left side and is linked to the peptide LRRLRRRLLR (SEQ ID NO:11).
  • EPA indicates a moiety derived from 5,8,11,14,17-eicosapentaenoic acid
  • DHA indicates a moiety derived from 4,7,10,13,16,19-docosahexaenoic acid.
  • (fish oil) indicates that the fatty acids in fish oil, including, but not limited to, fish oil components such as EPA and DHA, are linked to linked to the peptide LRRLRRRLLR (SEQ ID NO:11).
  • the synthetic ApoE-mimicking peptide is a mixture of peptides comprising fatty acid groups derived from the fish oil used to prepare them.
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide
  • the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ⁇ -amino fatty acid moiety, or an acetylated ⁇ -amino fatty acid moiety
  • the synthetic ApoE-mimicking peptide can be: 4-amino-butanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO: 648); 6-amino-hexanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO: 649); 8-amino-octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO: 650); 10-amino-decanoyl-LR
  • compositions comprising any one of the herein disclosed synthetic ApoE-mimicking peptides and a pharmaceutically acceptable carrier.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein the synthetic apolipoprotein E-mimicking peptide is administered as a composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein binding of LDL to a cell of the subject is enhanced.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein degradation of LDL by a cell of the subject is increased.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein LDL cholesterol in the subject is lowered.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein binding of VLDL to a cell of the subject is enhanced.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein degradation of VLDL by a cell of the subject is increased.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein VLDL cholesterol in the subject is lowered.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein total plasma concentration of cholesterol in the subject is lowered.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein said synthetic apolipoprotein E-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein the subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, peripheral artery disease (PAD), cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
  • a subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, peripheral artery disease (PAD), cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
  • Also disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein the synthetic apolipoprotein E-mimicking peptide is administered as a composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein binding of LDL to a cell of the subject is enhanced.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein degradation of LDL by a cell of the subject is increased.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein LDL cholesterol in the subject is lowered.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein binding of VLDL to a cell of the subject is enhanced.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein VLDL cholesterol in the subject is lowered.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein total plasma concentration of cholesterol in the subject is lowered.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein said synthetic apolipoprotein E-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein the subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
  • Also disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein the synthetic apolipoprotein E-mimicking peptide is administered as a composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein binding of LDL to a cell of the subject is enhanced.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein degradation of LDL by a cell of the subject is increased.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein LDL cholesterol in the subject is lowered.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein binding of VLDL to a cell of the subject is enhanced.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein VLDL cholesterol in the subject is lowered.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein total plasma concentration of cholesterol in the subject is lowered.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein said synthetic apolipoprotein E-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein the subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
  • Disclosed are methods for treating a subject with a Lipid Disorder the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein the synthetic apolipoprotein E-mimicking peptide is administered as a composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
  • Disclosed are methods for treating a subject with a Lipid Disorder the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein said synthetic apolipoprotein E-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.
  • Disclosed are methods for treating a subject with a Lipid Disorder the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein the lipid disorder is coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
  • dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of any of the disclosed Apo E-mimicking peptides to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase.
  • the treatment cycle comprises administration of an effective amount of the Apo E-mimicking peptide once a week for three months.
  • the treatment cycle comprises administration of an effective amount of the Apo E-mimicking peptide once every two weeks for up to 12 weeks.
  • dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of any of the disclosed Apo E-mimicking peptides to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase, wherein the dosing regimen further comprises a second treatment cycle after the rest phase.
  • Also disclosed are methods of treating acute coronary syndrome (ACS) comprising administering to a subject an effective amount of any of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase.
  • ACS acute coronary syndrome
  • ACS acute coronary syndrome
  • the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, wherein the rest phase is at least four weeks.
  • ACS acute coronary syndrome
  • the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase.
  • the second treatment cycle can be administered after a four week rest phase.
  • the second treatment cycle can be administered one year from the beginning of the initial treatment cycle.
  • ACS acute coronary syndrome
  • the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase, wherein an ACS therapeutic other than an Apo E-mimicking peptide is administered during the rest phase.
  • ACS acute coronary syndrome
  • ACS acute coronary syndrome
  • the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase, wherein an ACS therapeutic other than an Apo E-mimicking peptide is administered during the rest phase, wherein the ACS therapeutic other than an Apo E-mimicking peptide is a conventional LDL lowering therapy or HDL elevating therapy.
  • ACS acute coronary syndrome
  • the conventional LDL lowering therapy can be a statin.
  • the HDL elevating therapy can be an Apo A1 elevating drug, a CETP inhibitor, a phospholipase A2 inhibitor, an Apo A1 Milano, or an Apo A1 mimetic.
  • ACS acute coronary syndrome
  • the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase, wherein an ACS therapeutic other than an Apo E-mimicking peptide is administered during the rest phase, wherein the ACS therapeutic other than an Apo E-mimicking peptide is a conventional LDL lowering therapy or HDL elevating therapy, wherein the treatment cycle comprises administration of an effective amount of an Apo E-mimicking peptide once a week for three months.
  • the treatment cycle comprises administration of an effective amount of an Apo E-mimicking peptide once a week for three months.
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-AHA, wherein the receptor binding domain of apolipoprotein E is scrambled.
  • synthetic apolipoprotein E-mimicking peptides consisting of a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein receptor binding domain is covalently linked to said lipid-associating peptide, wherein both the receptor binding domain of apolipoprotein E and the lipid-associating peptide are scrambled.
  • FIG. 1 describes several strategies used to develop a highly effective peptide. From top to bottom in the “Sequence” column, the sequences are as follows: SEQ ID NO:664, 665, 666, 667, 668, 669, 670, 662, 671, 672, 673, 674.
  • FIGS. 2 A- 2 G shows the comparative analytical HPLC profiles of the indicated ApoE mimetic peptide analogs. Chromatography was carried out as follows: C-18 column-250 ⁇ 4.6 mm; mobile phase was a gradient of 30-70% acetonitrile in water over 35 minutes (with 0.1% TFA).
  • the baseline level is the relative plasma cholesterol level at the time of dose administration.
  • the time points show the plasma cholesterol levels at the indicated times following a single dose administration.
  • a single dose was administered using a saline vehicle.
  • FIG. 4 shows the comparative analytical HPLC profiles of three active ApoE mimetic peptide analogs. Chromatography was carried out as follows: C-18 column-250 ⁇ 4.6 mm; mobile phase was a gradient of 30-70% acetonitrile in water over 12 minutes (with 0.1% TFA).
  • FIGS. 5 A- 5 B shows representative data for the effect of three active ApoE mimetic peptide analogs in reducing plasma cholesterol (% reduction) at a dose level was either 50 ⁇ g ( FIG. 5 A ) or a dose level was either 100 ⁇ g ( FIG. 5 B ).
  • the data show that AC-Aha-[R]hE18A-NH 2 is highly effective in reducing plasma cholesterol in ApoE-null mice at both 50 and 100 ⁇ g/mouse.
  • FIG. 6 shows a model for CH 3 —(CH 2 ) n —CO-(apoE mimetic peptide) molecules to more avidly attach to a lipid particle than an apoE mimetic peptide that does not comprise an alkyl carboxyl moiety, and thus provides a model for enhanced hepatic clearance.
  • FIG. 7 is a table showing experimental design.
  • ApoE-null mice were dosed with the peptides Ac-he18A-NH 2 (AEM-28), Ac—[R]he18A-NH 2 (AEM-28(R)), or Ac-Aha-[R]he18A-NH 2 (AES-21), in saline via tail vein injection at a concentration of 100 ug/mouse.
  • Blood was collected via a cheek bleed at pre-dose, and at 1, 6 and 24 hours post dose. Serum samples can be analyzed for total serum cholesterol (using Waco total cholesterol kit).
  • FIGS. 8 A and 8 B are graphs showing total cholesterol (mg/dL) versus time ( FIG. 8 A ) and total cholesterol (% of pre-dose) versus time ( FIG. 8 B ), respectively.
  • FIG. 9 is a table showing the results from the mouse injections described in FIG. 8 .
  • FIG. 10 is a table showing the results of total serum cholesterol (as % of pre-dose level).
  • FIG. 11 shows an experimental design.
  • ApoE-null mice were dosed with AC-hE18A-NH2 (AEM-28), AC-[R]hE18A-NH2 (AEM-28(R)), or AC-Aha-[R]he18A-NH2 (AES2-21), in saline via tail vein injection at a concentration of 50 ⁇ g/mouse.
  • Blood was collected via a cheek bleed at pre-dose, and at 1, 6 and 24 hours post dose. Serum samples will be analyzed for total serum cholesterol (using a total cholesterol kit (Wako Chemicals USA, Inc., Richmond, Va.)).
  • FIGS. 12 A and 12 B are graphs showing total cholesterol (mg/dL) vs time and total cholesterol (% of pre-dose) vs time, respectively.
  • AEM-28 saline indicates the peptide AC-hE18A-NH2
  • AEM-28(R) saline indicates the peptide AC-[R]hE18A-NH2
  • AES2-21 indicates the peptide AC-Aha-[R]he18A-NH2.
  • FIG. 14 is a table showing % of pre-dose cholesterol.
  • FIG. 15 shows representative data for the plasma triglyceride profile in a sucrose-fed rat model.
  • the data show that following two weeks of a diet containing 65% (w/v) sucrose there was an increase in triglyceride levels.
  • the study was carried out in male Sprague-Dawley rats.
  • FIG. 16 show representative data for the effect of disclosed synthetic apolipoprotein E-mimicking peptides on triglyceride levels in rats fed a high sucrose (65% (w/v)) diet for two weeks at the indicated times post-administration of the indicated peptide (in saline vehicle) or control (saline) via a single dose (via intravenous tail vein injection).
  • Control indicates rats administered administered saline
  • AEM-28 indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac-hE18A-NH 2
  • R-AEM-28 indicates rats administered (i.v.
  • FIG. 17 show representative data for the effect of disclosed synthetic apolipoprotein E-mimicking peptides on triglyceride levels in rats fed a high sucrose (65% (w/v)) diet for two weeks at 48 h post-dosing with the indicated peptide or control (saline).
  • “Saline” indicates rats administered administered (i.v. via tail vein) saline;
  • “AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac-hE18A-NH 2 ;
  • R-AEM-28 indicates rats administered (i.v.
  • FIG. 18 show representative data for the effect of disclosed synthetic apolipoprotein E-mimicking peptides on plasm cholesterol levels in rats fed a high sucrose (65% (w/v)) diet for two weeks at 48 h post-dosing with the indicated peptide or control (saline).
  • “Saline” indicates rats administered administered (i.v. via tail vein) saline;
  • “AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac-hE18A-NH 2 ;
  • R-AEM-28 indicates rats administered (i.v.
  • FIG. 19 show representative data for the effect of disclosed synthetic apolipoprotein E-mimicking peptides on plasma glucose levels in rats at 48 h post-dosing with the indicated peptide (in saline vehicle) or control (saline).
  • the rats had been fed a high sucrose (65% (w/v)) diet for two weeks prior to peptide injection.
  • “Saline” indicates rats administered administered (i.v. via tail vein) saline
  • AEM-28 indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac-hE18A-NH 2
  • R-AEM-28 indicates rats administered (i.v.
  • FIGS. 20 A- 20 E shows representative analytical HPLC profiles for the indicated disclosed synthetic apolipoprotein E-mimicking peptides comprising a fatty acid moiety. Chromatography was carried out as follows: C-18 Vydac column-250 ⁇ 4.6 mm; mobile phase was a gradient of water/acetonitrile (0.1% TFA), 35-70% in 12 minutes.
  • FIG. 21 shows representative data for the effect of for disclosed synthetic apolipoprotein E-mimicking peptides comprising a fatty acid moiety on plasma cholesterol levels (% reduction in plasma cholesterol).
  • the peptides administered in this study were dialyzed following synthesis without further HPLC purification. Baseline levels are the plasma cholesterol levels at the time of peptide administration. All peptides were administered via intravenous tail vein injection.
  • FIG. 22 shows representative data for the effect of for disclosed synthetic apolipoprotein E-mimicking peptides comprising a fatty acid moiety on plasma cholesterol levels.
  • the study was otherwise carried out as described for FIG. 21 .
  • the indicated times are the times post-administration of a single 50 ⁇ g dose via intravenous tail vein injection.
  • FIG. 23 shows representative data for the effect of for disclosed synthetic apolipoprotein E-mimicking peptides comprising a fatty acid moiety on plasma cholesterol levels.
  • the study was otherwise carried out as described for FIG. 21 .
  • the indicated times are the times post-administration of a single 50 ⁇ g dose via intravenous tail vein injection.
  • FIG. 24 show representative dose response data for the effect of myristoyl-LRRLRRRLLR-18A-NH2 (i.e., myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628)) on plasma cholesterol levels.
  • the indicated doses were administered via intravenous tail vein injection.
  • FIG. 25 show representative dose response data for the effect of myristoyl-LRRLRRRLLR-18A-NH2 (i.e., myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628)) on plasma cholesterol levels.
  • the indicated doses were administered via intravenous tail vein injection.
  • FIG. 26 shows data from the study described for FIG. 25 replotted in terms of maximum percent decrease in plasma cholesterol (at 5 hr) versus dose level ( ⁇ g). The data are show as closed circles with the line the result of a hyperbolic curve fit to the data.
  • FIG. 27 shows data from the study described for FIG. 25 replotted in terms of the percent decrease in plasma cholesterol at 24 hr versus dose level ( ⁇ g). The data are show as closed circles with the line the result of a hyperbolic curve fit to the data.
  • FIG. 28 show representative dose response data for the effect of octanoyl-LRRLRRRLLR-18A-NH2 (i.e., octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625)) on plasma cholesterol levels (mg/dL).
  • the indicated doses were administered via intravenous tail vein injection.
  • FIG. 29 show representative dose response data for the effect of octanoyl-LRRLRRRLLR-18A-NH2 (i.e., octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625)) on plasma cholesterol levels (percent of baseline plasma cholesterol levels).
  • the baseline level is the plasma cholesterol level at the time of the peptide administration.
  • the indicated doses were administered via intravenous tail vein injection.
  • FIG. 30 shows data from the study described for FIGS. 28 - 29 replotted in terms of maximum percent decrease in plasma cholesterol (at 5 hr) versus dose level ( ⁇ g). The data are show as closed circles with the line the result of a hyperbolic curve fit to the data.
  • FIG. 31 shows data from the study described for FIGS. 28 - 29 replotted in terms of the percent decrease in plasma cholesterol at 24 hr versus dose level ( ⁇ g). The data are show as closed circles with the line the result of a hyperbolic curve fit to the data.
  • Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value.
  • the term “about” is used herein to mean approximately, in the region of, roughly, or around.
  • the term “about” modifies that range by extending the boundaries above and below the numerical values set forth.
  • the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%.
  • another embodiment includes from the one particular value and/or to the other particular value.
  • values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • amino acid sequence refers to a list of abbreviations, letters, characters or words representing amino acid residues.
  • the amino acid abbreviations used herein are conventional one letter codes for the amino acids and are expressed as follows: A, alanine; C, cysteine; D aspartic acid; E, glutamic acid; F, phenylalanine; G, glycine; H histidine; I isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; and Y, tyrosine.
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more —OCH 2 CH 2 O— units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more —CO(CH 2 ) 8 CO— moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • C n As defined herein, “C n ,” where “n” is an integer, describes a hydrocarbon molecule or fragment (e.g., an alkyl group) wherein “n” denotes the number of carbon atoms in the fragment or molecule.
  • fatty acid includes saturated fatty acids, which do not contain any double or triple bonds in the hydrocarbon chain.
  • Saturated fatty acids include, but are not limited to propionic acid (C3) (by way of example, C3 indicates propionic acid has 3 carbon atoms in its hydrocarbon chain; the number of carbon atoms in the hydrocarbon chain of other example fatty acids is denoted in analogous fashion herein), butyric acid (C4), valeric acid (C5), caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16), margaric acid (C17), stearic acid (C18), isostearic acid (C18), nonadecylic acid (C3)
  • C3
  • fatty acid also includes monounsaturated fatty acids, which contain one double or triple bond in the hydrocarbon chain, and polyunsaturated fatty acids, which contain more than one double and/or triple bond in the hydrocarbon chain.
  • Such acids include, but are not limited to the omega 3, omega 6, omega 9 fatty acids, other fatty acids such as myristoleic and palmitoleic acid and conjugated fatty acids.
  • Examples of monounsaturated and polyunsaturated fatty acids include but are not limited to, (a) omega 3 fatty acids, such as hexadecatrienoic acid (C16:3); (by way of example, C16:3 indicates hexadecatrienoic acid has 16 carbon atoms in its hydrocarbon chain and 3 double bonds; the number of carbon atoms and double bonds in the hydrocarbon chain of other example unsaturated fatty acids is denoted in analogous fashion herein), alpha linolenic acid (C18:3) and eicosapentanoic acid (20:5), (b) omega 6 fatty acids, such as linoleic acid (18:2), docosadienoic acid (C22:2), arachidonic acid (C20:4) and tetracosatetraenoic acid (C24:5), (c) omega 9 fatty acids, such as oleic acid (C18:1), eicosenoic acid (C20:1) and
  • fatty acid also includes branched fatty acids.
  • branched fatty acids include, but are not limited to, monomethyl branched fatty acids, such as 14-methyl pentadecanoic acid, 6-methyl caprylic acid, 4-methyl-3-pentenoic acid, (pyroterebic acid), 2-methyl-2E-butenoic acid (tiglic acid), 2-methyl-2Z-butenoic acid (angelic acid), multimethyl branched acids, isoprenoid fatty acids (vittatalactone, all-trans-retinoic acid), branched methoxy fatty acids and hydroxy and other fatty acids such as 2-hydroxyoctanoic acid and 4-oxopentanoic acid (levulinic acid).
  • monomethyl branched fatty acids such as 14-methyl pentadecanoic acid, 6-methyl caprylic acid, 4-methyl-3-pentenoic acid, (pyroterebic acid), 2-methyl-2E-butenoic acid (tiglic acid), 2-methyl-2Z-butenoic
  • fatty acid also includes mixtures comprising fatty acids such as natural oils or fats which may comprise components that are not fatty acids.
  • Natural oils or fats understood to comprise mixtures of fatty acids include, but are not limited to, animal fats, soya bean oil, coconut oil, palm oil, palm kernel oil, rapeseed oil, cottonseed oil, linseed oil, sunflower oil, fish oil, algae oil, and the like.
  • ⁇ -amino-fatty acid refers to fatty acids which feature an amino group at the distal carbon of the hydrocarbon chain thereof.
  • the ⁇ -amino-fatty acid moieties that are used in the context of the present invention can be saturated or unsaturated hydrocarbon chains. These moieties have a carboxylic group at one end of the hydrocarbon chain and an amine group at the other.
  • the hydrocarbon chain connecting the carboxylic and amine groups in such an ⁇ -amino-fatty acid moiety typically has from 3 to 32 carbon atoms.
  • Exemplary ⁇ -amino-fatty acids include, without limitation, 4-amino-butyric acid, 6-amino-caproic acid, 8-amino-caprylic acid, 10-amino-capric acid (10-amino-decanoic acid), 12-amino-lauric acid (12-amino-dodecanoic acid), 14-amino-myristic acid (14-amino-tetradecanoic acid), 14-amino-myristoleic acid, 16-amino-palmitic acid (16-amino-hexadecanoic acid), 18-amino-stearic acid, 18-amino-oleic acid, 16-amino-palmitoleic acid, 18-amino-linoleic acid, 18-amino-linolenic acid and 20-amino-arachidonic acid.
  • Dosing regimen refers to at least one treatment cycle followed by at least one rest phase.
  • a dosing regimen can include more than one treatment cycle and more than one rest phase.
  • a dosing regimen can be a three month treatment cycle followed by a one year rest phase.
  • Another example can be a six month treatment cycle followed by a six month rest phase and then a three month treatment cycle followed by a one year rest phase.
  • Dose or “dosage” as used herein refers to a specific quantity of a therapeutic agent, such as an Apo E mimetic, that is taken at specific times.
  • treat is meant to mean administer one of the disclosed compositions to a subject, such as a human or other mammal (for example, an animal model), that has atherosclerosis, in order to prevent or delay a worsening of the effects of the disease or condition, or to partially or fully reverse the effects of the disease.
  • a subject such as a human or other mammal (for example, an animal model), that has atherosclerosis, in order to prevent or delay a worsening of the effects of the disease or condition, or to partially or fully reverse the effects of the disease.
  • prevent is meant to mean minimize the chance that a subject who has an increased susceptibility for developing atherosclerosis will develop atherosclerosis.
  • treatment cycle refers to the administration of Apo E mimetics for an established period of time.
  • a treatment cycle includes a wide range of dosages of Apo E mimetics as well as different lengths of time for administering the Apo E mimetics.
  • a treatment cycle can be a three month period wherein an Apo E mimetic is administered twice a week for the three month period.
  • an effective amount of an Apo E mimetic can be an amount that provides a therapeutic affect and provides sustained therapeutic effects after withdrawal of the treatment.
  • An effective amount of an Apo E mimetic is an amount that is able to cause a benefit illustrated by a decrease in atherosclerosis, a decrease in artery wall stiffness, a decrease in isolated systolic hypertension, a decrease in arterial inflammation, an increase in anti-oxidant capability of the HDL fraction and/or an improvement in myocardial function, as well as an amount that allows for a sustained therapeutic effect after withdrawal of the Apo E mimetic.
  • an appropriate “effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.
  • sustained therapeutic effect is a therapeutic effect that persists after the therapeutic has been withdrawn. For example, the sustained therapeutic effect is maintained even after the acute cholesterol lowering effect is gone.
  • Rapid phase refers to a period of time wherein an Apo E mimetic is not administered.
  • Atherosclerotic burden is the amount of atherosclerosis in the arteries of a patient. This may include the coronary, carotid, peripheral and other arteries.
  • the atheroma may be complex lesions with a smooth muscle and collagen containing fibrous cap, areas of calcification, cholesterol crystals and cholesterol laden macrophages (foam cells) and/or less complex and more unstable lesions with less calcification and a thinner fibrous cap, and more foam cells and cholesterol (unstable lesions).
  • the unstable lesions may intrude into the lumen of the artery or expand away from the lumen of the artery.
  • lipid disorder is meant to mean when a subject has an excess of lipids or increased inflammatory lipids in their blood.
  • Lipids include, but are not limited to lipids such as ox-LDL (i.e., oxidized PAPC (1-palmitoyl 2-arachidonyl phophyatidyl choline)). Oxidation of PAPC or PLPC, the lipid components of LDL, produce oxidized lipids. Having a lipid disorder can make one more likely to develop inflammatory disease such as atherosclerosis and heart disease. Lipid disorders can be caused by genetic predispositions or diet.
  • lipoprotein or “lipoproteins” is meant to mean a biochemical assembly that contains both proteins and lipids.
  • the lipids or their derivatives may be covalently or non-covalently bound to the proteins.
  • Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins. Examples include the high density and low density lipoproteins of the blood, the transmembrane proteins of the mitochondrion and the chloroplast, and bacterial lipoproteins
  • high-density lipoprotein is meant to mean a class of lipoproteins, varying somewhat in their size (8-11 nm in diameter), that can transport cholesterol.
  • HDL cholesterol is cholesterol that is associated with HDLs. About one-fourth to one-third of blood cholesterol is carried by high-density lipoprotein (HDL).
  • HDL cholesterol is known as “good” cholesterol, because high levels of HDL seem to protect against heart attack.
  • Low levels of HDL (less than 40 mg/dL in men and less than 50 mg/dL in women) also increase the risk of heart disease. Medical experts think that HDL tends to carry cholesterol away from the arteries and back to the liver, where it is passed from the body. Some experts believe that that HDL removes excess cholesterol from arterial plaque, thus slowing its buildup
  • VLDL very Low Density Lipoproteins
  • LDL low density lipoprotein
  • low-density lipoprotein or “LDL” is meant to mean a lipoprotein that varies in size (approx. 22 nm) and can contain a changing number of triglycerides and cholesteryl esters they actually have a mass and size distribution.
  • Each native LDL particle contains a single apolipoproteinB-100 molecule (Apo B-100, a protein with 4536 amino acid amino acid residues) and a phospholipid coat that circles the triglycerides and cholesteryl esters, keeping them soluble in the aqueous environment.
  • LDL is commonly referred to as bad cholesterol.
  • LDL cholesterol is cholesterol that is associated with LDLs.
  • LDL cholesterol When too much LDL cholesterol circulates in the blood, it can slowly build up in the inner walls of the arteries that feed the heart and brain. Together with other substances, it can form plaque, a thick, hard deposit that can narrow the arteries and make them less flexible. This condition is known as atherosclerosis. If a clot forms and blocks a narrowed artery, then heart attack or stroke can result.
  • Cholesterol cannot dissolve in the blood. It has to be transported to and from the cells by carriers called lipoproteins. LDLs and HDLs along with triglyceride-rich lipoproteins (VLDL) and Lp(a) cholesterol, make up your total cholesterol count, which can be determined through a blood test.
  • VLDL triglyceride-rich lipoproteins
  • Lp(a) cholesterol make up your total cholesterol count, which can be determined through a blood test.
  • nucleic acid refers to a naturally occurring or synthetic oligonucleotide or polynucleotide, whether DNA or RNA or DNA-RNA hybrid, single-stranded or double-stranded, sense or antisense, which is capable of hybridization to a complementary nucleic acid by Watson-Crick base-pairing.
  • Nucleic acids of the invention can also include nucleotide analogs (e.g., BrdU), and non-phosphodiester internucleoside linkages (e.g., peptide nucleic acid (PNA) or thiodiester linkages).
  • nucleic acids can include, without limitation, DNA, RNA, cDNA, gDNA, ssDNA, dsDNA or any combination thereof
  • apolipoprotein E-mimicking peptides or Apo E mimetics Disclosed are apolipoprotein E-mimicking peptides or Apo E mimetics.
  • Non-limiting examples of the Apo E-mimicking peptides are provided herein.
  • the Apo E-mimicking peptides can be single domain or dual domain peptides.
  • Compositions containing the Apo E-mimicking peptides are also disclosed.
  • RNA-binding peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an acetylated amino hexanoic acid (Ac-Aha).
  • lipid-associating peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide
  • the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the Ac-Aha is at the N-terminus of the peptide.
  • the Aha can be inserted between the lipid-associating peptide comprises a class A amphipathic-helical domain.
  • the class A amphipathic-helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
  • apolipoprotein E can be from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
  • LRKLRKRLLR SEQ ID NO:4
  • LRRLRRRLLR SEQ ID NO:11
  • LRKMRKRLMR SEQ ID NO:7
  • RLTRKRGLK SEQ ID NO:13
  • the receptor binding domain of ApoE can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO:4), LRKLPKRLLR (SEQ ID NO:8), LRNVRKRLVR (SEQ ID NO:9), MRKLRKRVLR (SEQ ID NO:10), LRRLRRRLLR (SEQ ID NO:11), LRKLRKRFFR (SEQ ID NO:12), LRKLRKRLLR (SEQ ID NO:4), or LRKMRKRLMR (SEQ ID NO:7).
  • LRKLRKRLLR SEQ ID NO:4
  • LRRLRRRLLR SEQ ID NO:11
  • LRKMRKRLMR SEQ ID NO:7
  • RLTRKRGLK SEQ ID NO:13
  • LRRMRRRLMR SEQ ID NO:621
  • RLTRRRGK RLTRRRGK
  • the ApoE-mimicking peptide of Ac-Aha-hE18A-NH 2 is Ac-Aha-LRKLRKRLLR-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO:1).
  • the ApoE-mimicking peptide of Ac-Aha-[R]hE18A-NH 2 is Ac-Aha-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 . (SEQ ID NO:662)
  • the ⁇ -amino fatty acid moiety can be inserted between the lipid-associating peptide comprises a class A amphipathic-helical domain.
  • the class A amphipathic-helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
  • apolipoprotein E can be from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
  • RNA binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), or RLTRKRGLK (SEQ ID NO:13).
  • the receptor binding domain of ApoE can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO:4), LRKLPKRLLR (SEQ ID NO:8), LRNVRKRLVR (SEQ ID NO:9), MRKLRKRVLR (SEQ ID NO:10), LRRLRRRLLR (SEQ ID NO:11), LRKLRKRFFR (SEQ ID NO:12), LRKLRKRLLR (SEQ ID NO:4), or LRKMRKRLMR(SEQ ID NO:7).
  • LRKLRKRLLR SEQ ID NO:4
  • LRRLRRRLLR SEQ ID NO:11
  • LRKMRKRLMR SEQ ID NO:7
  • RLTRKRGLK SEQ ID NO:13
  • LRRMRRRLMR SEQ ID NO:621
  • RLTRRRGK RLTRRRGK
  • fatty acid moiety is shown at the left side and is linked to the peptide LRRLRRRLLR (SEQ ID NO:11).
  • EPA indicates a moiety derived from 5,8,11,14,17-eicosapentaenoic acid
  • DHA indicates a moiety derived from 4,7,10,13,16,19-docosahexaenoic acid.
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide
  • the synthetic ApoE-mimicking peptide comprises a fatty acid moiety derived from a natural oil or fat, e.g. fish oil
  • the synthetic ApoE-mimicking peptide can be: (fish oil)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO:663).
  • (fish oil) indicates that the fatty acids in fish oil, including, but not limited to, fish oil components such as EPA and DHA, are linked to linked to the peptide LRRLRRRLLR (SEQ ID NO:11).
  • the synthetic ApoE-mimicking peptide is a mixture of peptides comprising fatty acid groups derived from the fish oil used to prepare them.
  • the synthetic ApoE-mimicking peptide can be any of the disclosed peptides comprising a fatty acid.
  • the synthetic ApoE-mimicking peptide can be any of the disclosed peptides comprising an acetylated fatty acid.
  • synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of apolipoprotein E is scrambled. Examples of scrambled receptor binding domains of ApoE are provided below.
  • synthetic apolipoprotein E-mimicking peptide consisting of: a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein receptor binding domain is covalently linked to said lipid-associating peptide, wherein both the receptor binding domain of apolipoprotein E and the lipid-associating peptide are scrambled.
  • Examples of scrambled receptor binding domains of ApoE and scrambled lipid-associating peptides are provided below.
  • Apolipoprotein E-mimicking peptides have both direct cholesterol lowering effects by providing an alternative ligand for receptors on the liver to clear atherogenic Apolipoprotein B containing lipoproteins (LDL, VLDL, and ⁇ -VLDL), and direct beneficial effects on the artery wall.
  • LDL, VLDL, and ⁇ -VLDL Apolipoprotein B containing lipoproteins
  • New, more effective methods of imaging coronary atherosclerosis allow for direct measurement of benefits to the artery wall (Van Velzen, et al. Hellenic J Cardiol 50: 245-263, 2009).
  • the Apo E-mimicking peptides can enhance the removal of cholesterol from the artery wall, working in conjunction with HDL, increasing the formation of lipid poor pre ⁇ -HDL that accept cholesterol from macrophages.
  • the Apo E-mimicking peptides can stimulate macrophage-mediated clearance of dead and dying cells in the artery wall (efferocytosis), improve the quality of HDL by increasing PON-1 levels and bringing down plasma lipid hydroperoxide levels, decrease macrophage content in atherosclerotic lesions resulting in more stable lesions, and decrease inflammation in the artery wall.
  • the Apo E-mimicking peptides reduce the size of atherosclerotic lesions more rapidly than apoA-I mimetic peptides and more rapidly than the statins (HMG-CoA reductase inhibitors). Atherosclerotic lesion regression persists in Apo E-mimicking peptides treated animals even when cholesterol levels are the same as in saline treated animals. Thus, the effects cannot be simply explained by cholesterol lowering.
  • Apolipoprotein E plays an important role in the metabolism of triglyceride-rich lipoproteins, such as very low density lipoprotein (VLDL) and chylomicrons.
  • Apolipoprotein E mediates the high affinity binding of Apo E-containing lipoproteins to the low density lipoprotein (LDL) receptor (Apo B, E receptor) and the members of its gene family, including LDL receptor related protein (LRP), very low density lipoprotein receptor (VLDLR) and the Apo E2 receptor (Apo E2R) (Mahley, R. W., (1988) Science 240, 622-630).
  • mice that over express human Apo E have lower levels of total plasma cholesterol levels (Shimono, H. N., et al., (1992) Eur. J. Clin. Invest. 90, 2084-2991), (ii) intravenous injection of human Apo E into cholesterol-fed rabbits protects these animals from atherosclerosis (Yamada, et al., (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 665-669), and (iii) loss of the Apo E gene in mice produces spontaneous atherosclerosis (Zhang, S.
  • Apo E is a protein that binds lipid and has two major domains (Mahley, R. W., et al. J. Lipid Res. 1999, 40:622-630).
  • the 22 kDa amino terminal domain has been shown by X-ray crystallographic studies to be a 4-helix bundle (Wilson, C., et al. Science 1991; 252:1817-1822) and to contain a positively-charged receptor binding domain.
  • VLDL very low-density lipoprotein
  • the VLDL is defective in binding to receptors.
  • the positively charged arginine (Arg)-rich cluster domain of the Apo E and the C-terminal amphipathic helical domain are both required for the enhanced uptake of atherogenic Apo E-containing lipoproteins.
  • Apo E is secreted as a 299 amino acid residue protein with a molecular weight of 34,200. Based on thrombin cleavage of Apo E into two fragments, a two-domain hypothesis was initially suggested to explain the fact that the C-terminal region of Apo E (192-299) is essential for its binding to hypertriglyceridemic VLDL and the N-terminal 22 kDa domain (1-191), binds to the LDL-R (Bradley, W. A., et al., (1986) J. Lipid Res. 27, 40-48).
  • a minimal arginine-rich Apo E receptor binding domain (141-150) was sufficient to enhance low density lipoprotein (LDL) and very low density lipoprotein (VLDL) uptake and clearance when covalently linked to a class A amphipathic helix
  • a peptide was synthesized in which the receptor binding domain of human Apo E, LRKLRKRLLR (SEQ ID NO:4) (hApo E[141-150] also referred to as “hE”), was linked to 18A, a well characterized high affinity lipid-associating peptide (DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), also referred to as “18A”) to produce a peptide denoted as hApo E[141-150]-18A (also referred to as “hE-18A”) (see U.S.
  • LRP LDL receptor related protein
  • the minimal 141-150 Arg-rich domain did not decrease LDL levels but did so only in combination with 18A lipid associating domain, did not confer LDL-receptor binding but directed the LDL-peptide complex to the HSPG pathway for uptake and degradation by fibroblasts.
  • the disclosed peptides can be linked to a fatty acid moiety, an ⁇ -amino fatty acid moiety, or an acetylated ⁇ -amino fatty acid moiety.
  • the fatty acid moiety, the ⁇ -amino fatty acid moiety, or the acetylated ⁇ -amino fatty acid moiety is linked to a disclosed peptide via the N-terminal amino group of the peptide.
  • the linkage between the fatty acid moiety, the ⁇ -amino fatty acid moiety, or the acetylated ⁇ -amino fatty acid moiety and the N-terminal amino group of the peptide has the a structure represented by the following formulas, respectively:
  • A is an aliphatic group have 2-32 carbon atoms.
  • the aliphatic group is an alkyl group.
  • the aliphatic group comprises 0-3 double bonds.
  • the aliphatic group is an alkenyl group.
  • the fatty acid moiety linked to the disclosed peptide is derived from a purified fatty acid. In a still further aspect, the fatty acid moiety linked to the disclosed peptide is derived from a saturated fatty acid. In a yet further aspect, the fatty acid moiety linked to the disclosed peptide is derived from an unsaturated fatty acid. In an even further aspect, the unsaturated fatty acid is a polyunsaturated fatty acid with two or more double bonds.
  • the synthetic ApoE-mimicking peptide comprises a fatty acid moiety.
  • Exemplary fatty acids from which a fatty acid moiety is derived include, without limitation, butyric acid, caproic acid, caprylic acid, capric acid, decanoic acid, lauric acid, myristic acid, palmitic acid, pentadecanoic acid, stearic acid, arachidic acid, behenic acid, erucic acid, lignoceric acid, margaric acid, myristoleic acid, palmitoleic acid, oleic acid, gadoleic acid, ricinoleic acid, vaccenic acid, linoleic acid, linolenic acid, alpha-linolenic acid, gamma-linolenic acid, licanic acid, margaroleic acid, arachidic acid, gadoleic acid, nervonic acid, arachidonic acid, docosapentaenoic (DPA), eicosapentaenoic acid (EPA), docosahe
  • Exemplary saturated fatty acids include, but are not limited to, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic
  • Exemplary unsaturated fatty acids include, but are not limited to, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, linoleic acid, ⁇ -linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA), erucic acid, docosahexaenoic acid (DHA), and docosapentaenoic acid.
  • the fatty acid moiety linked to the disclosed peptide is derived from an unpurified fatty acid or mixture of fatty acids such as natural oil or fat.
  • a natural oil or fat is a heterogeneous mixture of generally hydrophobic compounds comprising one or more fatty acids.
  • the fatty acid source may comprise a natural oil or fat, such as (but not limited to) animal fats, biological oils, or vegetable oils such as soya bean oil, coconut oil, palm oil, palm kernel oil, rapeseed oil, cottonseed oil, linseed oil, sunflower oil, fish oil, algae oil, and the like.
  • the natural oil or fat is one that contains or is enriched for one or more omega-3 fatty acids, for example, marine oil, for example, fish oil, krill oil and algae oil. Any oil containing DHA and/or EPA can be used.
  • the natural oil or fat contains at least 70% or about 70%, by weight, DHA, for example, at least 75% or about 75%, at least 80% or about 80%, at least 85% or about 85%, or at least 90% or about 90%, by weight, DHA.
  • the natural oil or fat contains between 5% or about 5% and 15% or about 15% EPA, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15%, by weight, EPA.
  • the natural oil or fat contains not more than 10% or about 10% EPA or less than 10% or about 10%, EPA.
  • the fatty acid moiety is derived from an omega-3 fatty acid.
  • omega-3 polyunsaturated fatty acid(s) or “omega-3 fatty acid” refers to a family of unsaturated fatty carboxylic acids that have in common a carbon-carbon bond in the n-3 position (i.e., the third bond from the methyl end of the molecule). Typically, they contain from about 16 to about 24 carbon atoms and from three to six carbon-carbon double bonds. Omega-3 polyunsaturated fatty acids can be found in nature, and these natural omega-3 polyunsaturated fatty acids frequently have all of their carbon-carbon double bonds in the cis-configuration.
  • omega-3 fatty acids include, but are not limited to, 7,10,13-hexadecatrienoic acid (sometimes abbreviated as 16:3 (n-3)); 9,12,15-octadecatetrienoic acid ( ⁇ -linolenic acid (ALA), 18:3 (n-3)); 6,9,12,15-octadecatetraenoic acid (stearidonic acid (STD), 18:4 (n-3)); 11,14,17-eicosatrienoic acid (eicosatrienoic acid (ETE), 20:3 (n-3)); 8,11,14,17-eicosatetraenoic acid (eicosatetraenoic acid (ETA), 20:4 (n-3)); 5,8,11,14,17-eicosapentaenoic acid (eicosapentaenoic acid (EPA), (20:5 (n-3)); 7,10,13,16,19-docosapentaenoic acid (docosapent
  • a fatty acid comprises a chain length between C6 and C24, C10 and C24, C10 and C28, or C10 and C32, including synthetic fatty acids with odd carbon numbers.
  • a fatty acid comprises a chain length selected from the group consisting of: C10, C12, C14, C16, C18, C20, C20, C22 and C24.
  • the fatty acid has a chain length selected from the group consisting of C14, C16 and C18.
  • the fatty acid has a chain length selected from the group consisting of C13, C15 and C17.
  • the fatty acid has between 4 and 28 carbons.
  • the fatty acid aliphatic chain comprises 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 carbon atoms.
  • the fatty acid is a naturally-occurring fatty acid.
  • the fatty acid is a short chain fatty acid (e.g., less than six carbons), a medium chain fatty acid (e.g., 6-12 carbons), long chain fatty acids (e.g., longer than 12 carbons), or a very long chain fatty acid (e.g., longer than 22 carbons).
  • the fatty acid is an unsaturated fatty acid in the cis configuration.
  • the fatty acid is an unsaturated fatty acid in the trans configuration.
  • the synthetic ApoE-mimicking peptide comprises a ⁇ -amino fatty acid moiety.
  • Exemplary ⁇ -amino-fatty acid moieties are derived from ⁇ -amino-fatty acids including, without limitation, 4-amino-butyric acid, 6-amino-caproic acid, 8-amino-caprylic acid, 10-amino-capric acid (10-amino-decanoic acid), 12-amino-lauric acid (12-amino-dodecanoic acid), 14-amino-myristic acid (14-amino-tetradecanoic acid), 14-amino-myristoleic acid, 16-amino-palmitic acid (16-amino-hexadecanoic acid), 18-amino-stearic acid, 18-amino-oleic acid, 16-amino-palmitoleic acid, 18-amino-linoleic acid, 18-amino-linolenic acid and 20-amino-arachidonic acid.
  • the ⁇ -amino-fatty acids including
  • the ⁇ -amino fatty acid moiety is 4-amino-butanoyl, 6-amino-caproyl, 8-amino-octanoyl, 10-amino-decanoyl, 12-amino-lauroyl, 14-amino-myristoyl, 14-amino-myristoleoyl, 16-amino-palmiteoyl, 18-amino-stearoyl, 18-amino-oleoyl, 16-amino-palmitoleoyl, 18-amino-linoleoyl, 18-amino-linolenoyl, or 20-amino-arachidonoyl.
  • ⁇ -amino fatty acid moiety is 6-amino-caproyl (or alternatively referred to as 6-amino hexanoyl).
  • the ⁇ -amino-fatty acid moiety is derived from a ⁇ -amino-fatty acid having the structure:
  • A is an aliphatic group have 2-32 carbon atoms.
  • the aliphatic group is an alkyl group.
  • the aliphatic group comprises 0-3 double bonds.
  • the aliphatic group is an alkenyl group.
  • A is —(CH 2 ) 5 —.
  • the ⁇ -amino-fatty acid moiety is linked to the peptide via the N-terminal amino group of the peptide, and following linking to the peptide, the ⁇ -amino-fatty acid moiety has the structure:
  • A is an aliphatic group have 2-32 carbon atoms.
  • the aliphatic group is an alkyl group.
  • the aliphatic group comprises 0-3 double bonds.
  • the aliphatic group is an alkenyl group.
  • A is —(CH 2 ) 5 —.
  • the synthetic ApoE-mimicking peptide comprises an acetylated ⁇ -amino fatty acid moiety.
  • the disclosed peptides can be linked any of the disclosed ⁇ -amino-fatty acids, and then further comprise an acetyl moiety on the ⁇ -amino group.
  • the ⁇ -amino-fatty acid moiety is linked to the peptide via the N-terminal amino group of the peptide, and following linking to the peptide, the ⁇ -amino group is acetylated, and the ⁇ -amino-fatty acid moiety has the structure:
  • A is an aliphatic group have 2-32 carbon atoms.
  • the aliphatic group is an alkyl group.
  • the aliphatic group comprises 0-3 double bonds.
  • the aliphatic group is an alkenyl group.
  • A is —(CH 2 ) 5 —.
  • the fatty acids from which the fatty acid moiety is derived are commercially available and can be prepared by different chemical methods (Recent Developments in the Synthesis of Fatty Acid Derivatives, Editors: Knothe G and Derksen J T B, AOCS Press 1999, ISBN 1-893997-00-6.)
  • the single-domain synthetic Apo E mimetics can consist of a receptor binding domain of Apo E or a lipid-associating peptide.
  • the receptor binding domain peptide for the synthetic Apo E mimetics can be a human receptor binding domain peptide of Apo E.
  • receptor binding domain peptide of the disclosed synthetic Apo E mimetics can comprise the amino acid sequence of LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), or LRKLRKRFFR (SEQ ID NO:12).
  • the receptor binding domain peptide of such synthetic Apo E mimetics can also be from a species selected from the group consisting of mouse, rabbit, monkey, rat, bovine, pig and dog.
  • receptor binding domain peptides that can be used in the disclosed synthetic Apo E mimetics are provided in Table 1.
  • the italicized residues in Table 1 indicate changes from the human sequence; however, the property of the amino acid is conserved.
  • the bold-italicized residues in Table 1 indicate the difference from the human sequence at that position.
  • the receptor binding domain peptide for the synthetic Apo E mimetics can also be the LDL receptor (LDLR) binding domain of apolipoprotein B (ApoB).
  • the LDL receptor (LDLR) binding domain of ApoB can have the sequence RLTRKRGLK (SEQ ID NO:13).
  • ApoB-100 is a 550,000 Da glycoprotein with nine amino acids (3359-3367) serving as the binding domain for the LDL receptor (Segrest et al., J. Lipid. Res. 42, pp. 1346-1367 (2001)).
  • LDL Upon binding to LDLR in clathrin coated pits, LDL is internalized via endocytosis and moves into the endosome where a drop in pH causes the receptor to dissociate from the LDL.
  • LDL receptor (LDLR) binding domain of ApoB when used with the disclosed peptides can also be altered and/or modified as described throughout this application for Apo E.
  • LDL receptor (LDLR) binding domain of ApoB can be used with the disclosed lipid-associating peptides, wherein the LDL receptor (LDLR) binding domain of ApoB is covalently linked to said lipid-associating peptide.
  • the LDL receptor (LDLR) binding domain of ApoB can be scrambled, reverse-oriented, can be part of a domain switched peptide as described below.
  • One class A peptide designated 18A (see, e.g., Anantharamaiah (1986) Meth. Enzymol, 128: 626-668) was modified as described herein to produce peptides orally administrable and highly effective at inhibiting or preventing one or more symptoms of atherosclerosis and/or other indications described herein. Without being bound by a particular theory, it is believed that the disclosed peptides can act in vivo by picking up seeding molecule(s) that mitigate oxidation of LDL.
  • class A peptides were made including, the peptide designated 4F, D4F, 5F, and D5F, and the like.
  • Various class A peptides inhibited lesion development in atherosclerosis-susceptible mice and rabbits.
  • the peptides show varying, but significant degrees of efficacy in mitigating one or more symptoms of the various pathologies described herein. A number of such peptides are illustrated in Table 2.
  • the peptides include variations of 4F (D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO:16) in Table 2), also known as L-4F, where all residues are L form amino acids) or D-4F where one or more residues are D form amino acids).
  • 4F D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO:16) in Table 2
  • L-4F L-4F, where all residues are L form amino acids
  • D-4F where one or more residues are D form amino acids
  • the C-terminus, and/or N-terminus, and/or internal residues can be blocked with one or more blocking groups as described herein.
  • peptides of Table 2 are illustrated with an acetyl group or an N-methylanthranilyl group protecting the amino terminus and an amide group protecting the carboxyl terminus, any of these protecting groups may be eliminated and/or substituted with another protecting group as described herein.
  • the peptides can comprise one or more D-form amino acids as described herein.
  • every amino acid (e.g., every enantiomeric amino acid) of the peptides of Table 2 is a D-form amino acid.
  • Table 2 is not fully inclusive.
  • other suitable class A amphipathic helical peptides can routinely be produced (e.g., by conservative or semi-conservative substitutions (e.g., D replaced by E), extensions, deletions, and the like).
  • one embodiment utilizes truncations of any one or more of peptides shown herein (e.g., peptides identified as 2F, 3F, 3F 14 , 4F, 5F, 6F, or 7F—in Table 2).
  • A-F-Y-D-K-V-A-E-K-L-K-E-A-F (amino acids 5-18 of SEQ ID NO:5) illustrates a peptide comprising 14 amino acids from the C-terminus of 18A comprising one or more D amino acids, while others illustrate other truncations.
  • peptides are also suitable. Such longer peptides may entirely form a class A amphipathic helix, or the class A amphipathic helix (helices) can form one or more domains of the peptide.
  • this invention contemplates multimeric versions of the peptides (e.g., concatamers).
  • the peptides illustrated herein can be coupled together (directly or through a linker (e.g., a carbon linker, or one or more amino acids) with one or more intervening amino acids).
  • Illustrative polymeric peptides include 18A-Pro-18A and the peptides in the following table (Table 2B), in certain embodiments comprising one or more D amino acids, more preferably with every amino acid a D amino acid as described herein and/or having one or both termini protected.
  • modified class A amphipathic helix peptides incorporate one or more aromatic residues at the center of the nonpolar face, e.g., 3F C ⁇ , (as present in 4F), or with one or more aliphatic residues at the center of the nonpolar face, e.g., 3F I ⁇ , see, e.g., Table 3.
  • the central aromatic residues on the nonpolar face of the peptide 3F C ⁇ due to the presence of ⁇ electrons at the center of the nonpolar face can allow water molecules to penetrate near the hydrophobic lipid alkyl chains of the peptide-lipid complex, which in turn would enable the entry of reactive oxygen species (such as lipid hydroperoxides) shielding them from the cell surface.
  • the peptides with aliphatic residues at the center of the nonpolar face e.g., 3F I ⁇ , can act similarly but not quite as effectively as 3F C ⁇ .
  • the peptides can convert pro-inflammatory HDL to anti-inflammatory HDL or make anti-inflammatory HDL more anti-inflammatory, and/or decrease LDL-induced monocyte chemotactic activity generated by artery wall cells equal to or greater than D4F or other peptides shown in Table 2.
  • Class A amphipathic helical peptides that have an amino acid composition identical to one or more of the class A amphipathic helical peptides described above.
  • this invention contemplates peptides having an amino acid composition identical to 4F.
  • this invention includes active agents that comprise a peptide that consists of 18 amino acids, where the 18 amino acids consist of 3 alanines (A), 2 aspartates (D), 2 glutamates (E), 4 phenylalanines (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W), and 1 tyrosine (Y); and where the peptide forms a class A amphipathic helix; and protects a phospholipid against oxidation by an oxidizing agent.
  • the peptides comprise least one “D” amino acid residue; and in certain embodiments, the peptides comprise all “D: form amino acid residues. A variety of such peptides are illustrated in Table 4.
  • Table 4 provides the sequences and identifier names for representative 18 amino acid length class A amphipathic helical peptides with the amino acid composition comprising 3 alanines (A), 2 aspartates (D), 2 glutamates (E), 4 phenylalanines (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W), and 1 tyrosine (Y).
  • Lipid-associating peptides can comprise a peptide that is 18 amino acids in length and forms a class A amphipathic helix where the peptide has the amino acid composition 2 aspartates, 2 glutamates, 4 lysines, 1 tryptophan, 1 tyrosine, no more than one leucine, no more than 1 valine, no less than 1 and no more than 3 alanines, and with 3 to 6 amino acids from the group: phenylalanine, alpha-naphthalanine, beta-naphthalanine, histidine, and contains either 9 or 10 amino acids on the polar face in a helical wheel representation of the class A amphipathic helix including 4 amino acids with positive charge at neutral pH with two of the positively charged
  • the acidic amino acids are glutamic acid rather than having two aspartic acids and two glutamic acids.
  • the lipid associating peptide can be 18A, wherein each of the acidic amino acids of 18A are Glu residues.
  • Class Y amphipathic helical peptides are known to those of skill in the art (see, e.g., Segrest et al. (1992) J. Lipid Res. 33: 141-166; Oram and Heinecke (2005) Physiol Rev. 85: 1343-1372, and the like). These peptides include, but are not limited to, an 18 amino acid peptide that forms a class A amphipathic helix or a class Y amphipathic helix described by formula I:
  • 4Nph (SEQ ID NO: 460) Ac-DW Nph KA Nph YDKVAEK Nph KEA Nph -NH2 [D-E switched] 4Nph (SEQ ID NO: 461) Ac- E W Nph KA Nph Y E KVADK Nph K D A Nph -NH2 [D > E]4Nph (SEQ ID NO: 462) Ac- E W Nph KA Nph Y E KVAEK Nph KEA Nph -NH2 [E > D]4Nph (SEQ ID NO: 463) Ac-DW Nph KA Nph YDKVA D K Nph K D A Nph -NH2 [D-1 > E]4Nph (SEQ ID NO: 464) Ac- E W Nph KA Nph YDKVAEK Nph KEA Nph -NH2 [D-8 > E]4Nph (SEQ
  • Rev-4Nph (SEQ ID NO: 474) Ac- Nph AEK Nph KEAVKDY Nph AK Nph WD-NH2 [F-3, 6 > Nph]Rev (SEQ ID NO: 475) Ac- Nph AEK Nph KEAVKDYFAKFWD-NH2 4F [F-13, 16]Rev-4F (SEQ ID NO: 476) Ac-FAEKFKEAVKDY Nph AK Nph WD-NH2 [F-3 > Nph]Rev-4F (SEQ ID NO: 477) Ac- Nph AEKFKEAVKDYFAKFWD-NH2 [F-6 > Nph]Rev-4F (SEQ ID NO: 478) Ac-FAEK Nph KEAVKDYFAKFWD-NH2 [F-13 > Nph]Rev-4F (SEQ ID NO: 479) Ac-FAEKFKEAVKDY Nph AKFWD-NH2 [F-16 > Np
  • any of the peptides described herein can comprise non-natural amino acids in addition to or instead of the corresponding the natural amino acids identified herein.
  • Such modifications include, but are not limited to acetylation, amidation, formylation, methylation, sulfation, and the like.
  • lipid-associating peptide consisting of a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a domain switched orientation to those described above and in Table 7.
  • the lipid-associating peptide is covalently linked to the receptor binding domain of apolipoprotein E such that the lipid-associating peptide is at the N-terminus of the synthetic apolipoprotein E-mimicking peptide.
  • the disclosed domain switched synthetic Apo E mimetics can also be N-terminally protected using acetyl and amino groups.
  • synthetic Apo E-mimicking peptides consisting of a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a reversed orientation.
  • synthetic Apo E-mimicking peptides consisting of a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein either the sequence of the receptor binding domain or the sequence of the lipid-associating peptide or both sequences are in the reversed orientation.
  • Table 9 provides non-limiting examples of the disclosed synthetic Apo E-mimicking peptides comprising a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a reversed orientation.
  • Non-limiting Examples of Synthetic Apo E mimetics Receptor Binding Domains of Apo E Lipid-Associating Peptides RLLRKRLKRL DWLKAFYDKVAEKLKEAF (SEQ ID NO: 609) (SEQ ID NO: 5) RLLRKRLKRL DWLKAFYDKVAEKLKEAF (SEQ ID NO: 609) (SEQ ID NO: 5) RLLRKRLKRL DWLKAFYDKVAEKLKEAF (SEQ ID NO: 609) (SEQ ID NO: 5) RMLRKRMKRL DWLKAFYDKVAEKLKEAF (SEQ ID NO: 610) (SEQ ID NO: 5) RMLRKRMKRL DWLKAFYDKVAEKLKEAF (SEQ ID NO: 610) (SEQ ID NO: 5) RMLRKRMKRL DWLKAFYDKVAEKLKEAF (SEQ ID NO: 5) RLLRKPLKRL DWLKAF
  • a synthetic apolipoprotein E-mimicking peptide consisting of: a receptor binding domain of apolipoprotein E comprising the amino acid sequence of D-W-L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F (SEQ ID NO:69); and a lipid-associating peptide, wherein said receptor binding domain is covalently linked to said lipid-associating peptide.
  • a synthetic Apo E-mimicking peptides comprising: a lipid binding domain of apolipoprotein E comprising the amino acid sequence of E-W-L-K-A-F-V-Y-E-K-V-F-K-L-K-E-F-F (SEQ ID NO:70) and a receptor binding domain peptide, wherein said lipid binding domain is covalently linked to said receptor binding domain peptide.
  • Table 10 provides non-limiting examples of the disclosed scrambled synthetic Apo E mimetics comprising a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein said receptor binding domain is covalently linked to said lipid-associating peptide, wherein the receptor binding domain of apolipoprotein E is scrambled.
  • the disclosed scrambled synthetic Apo E mimetics can also be N-terminally and C-terminally protected using acetyl and amide groups.
  • the disclosed scrambled synthetic Apo E mimetics can also be reverse-oriented as described above.
  • the peptide linkages can be selected from the group consisting of: —CH 2 NH—, —CH 2 S—, —CH 2 —CH 2 —, —CH ⁇ CH—(cis and trans), —COCH 2 —, —CH(OH)CH 2 —, —CH 2 SO—, etc. by methods known in the art and further described in the following references: Spatola (1983) p. 267 in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, eds., Marcel Dekker, New York; Spatola (1983) Vega Data 1(3) Peptide Backbone Modifications.
  • One particularly preferred non-peptide linkage is —CH 2 NH—.
  • Such peptide mimetics may have significant advantages over polypeptide embodiments, including, for example: more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), reduced antigenicity, and others.
  • the linker is a cleavable linker.
  • cleavable linkers include protease cleavable peptide linkers, nuclease sensitive nucleic acid linkers, lipase sensitive lipid linkers, glycosidase sensitive carbohydrate linkers, pH sensitive linkers, hypoxia sensitive linkers, photo-cleavable linkers, heat-labile linkers, enzyme cleavable linkers (e.g., esterase cleavable linker), ultrasound-sensitive linkers, x-ray cleavable linkers, etc.
  • protease cleavable peptide linkers include protease cleavable peptide linkers, nuclease sensitive nucleic acid linkers, lipase sensitive lipid linkers, glycosidase sensitive carbohydrate linkers, pH sensitive linkers, hypoxia sensitive linkers, photo-cleavable linkers, heat-labile linkers, enzyme cleavable linkers (e.g., este
  • the receptor binding domain or the lipid-associating peptide can be modified or altered as described above.
  • the receptor binding domain or the lipid-associating peptide can be mutated, scrambled, and/or reverse-oriented. Any other modifications or alterations disclosed herein for the dual-domain polypeptides can also be used for the single-domain peptides.
  • scrambled peptides can also be reverse-oriented, or can be in a switched orientation. Additionally, reverse-oriented peptides can be in a switched orientation. All other combinations of the disclosed peptides are also contemplated.
  • Non-limiting examples of the peptides have been described herein (see Tables 1-5, for example).
  • the term “analog” is used interchangeably with “variant” and “derivative.” Variants and derivatives are well understood to those of skill in the art and can involve amino acid sequence modifications. Such, amino acid sequence modifications typically fall into one or more of three classes: substantial; insertional; or deletional variants.
  • Insertions include amino and/or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily are smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues.
  • These variants ordinarily are prepared by site-specific mutagenesis of nucleotides in the DNA encoding the protein, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example M13 primer mutagenesis and PCR mutagenesis. Amino acid substitutions are typically of single residues, but can occur at a number of different locations at once.
  • substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final derivative or analog.
  • Substitutional variants are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with Tables 11 and 12 and are referred to as conservative substitutions.
  • substitutions that are less conservative than those in Table 11, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
  • substitutions which in general are expected to produce the greatest changes in the protein properties are those in which: (a) the hydrophilic residue, e.g.
  • seryl or threonyl is substituted for (or by) a hydrophobic residue, e.g., leucyl, isoleucyl, phenylalanyl, valyl or alanyl; Tryptophan, Tyrosinyl (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or hystidyl, is substituted for (or by) an electronegative residue, e.g.
  • Amino Acid Abbreviations Amino Acid Abbreviations Alanine Ala (A) Allosoleucine AIle Arginine Arg (R) Asparagine Asn (N) Aspartic Acid Asp (D) Cysteine Cys (C) Glutamic Acid Glu (E) Glutamine Gln (Q) Glycine Gly (G) Histidine His (H) Isolelucine Ile (I) Leucine Leu (L) Lysine Lys (K) Phenylalanine Phe (F) Praline Pro (P) Pyroglutamic Acid PGlu (U) Serine Ser (S) Threonine Thr (T) Tyrosine Tyr (Y) Tryptophan Trp (W) Valine Val (V)
  • variants and derivatives of the disclosed proteins herein are to define them in terms of homology/identity to specific known sequences.
  • variants of synthetic Apo E mimetics and other proteins or peptides herein disclosed which have at least, 70% or at least 75% or at least 80% or at least 85% or at least 90% or at least 95% homology to the synthetic Apo E mimetics specifically recited herein.
  • Those of skill in the art readily understand how to determine the homology of two proteins.
  • polypeptides can be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Modifications can occur anywhere in the polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. The same type of modification can be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide can have many types of modifications.
  • Modifications include, without limitation, acetylation, acylation, ADP-ribosylation, amidation, covalent cross-linking or cyclization, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of a phosphytidylinositol, disulfide bond formation, demethylation, formation of cysteine or pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristolyation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, and transfer-RNA mediated addition of amino acids to protein such as arginylation.
  • Variants can also include peptidomimetics.
  • peptidomimetic means a mimetic of a function of a protein which includes some alteration of the normal peptide chemistry.
  • Peptidomimetics typically are short sequences of amino acids that in biological properties mimic one or more function(s) of a particular protein. Peptide analogs enhance some property of the original peptide, such as increases stability, increased efficacy, enhanced delivery, increased half-life, etc. Methods of making peptidomimetics based upon a known polypeptide sequence is described, for example, in U.S. Pat. Nos. 5,631,280; 5,612,895; and 5,579,250.
  • peptidomimetics can involve the incorporation of a non-amino acid residue with non-amide linkages at a given position.
  • One embodiment of the present invention is a peptidomimetic wherein the compound has a bond, a peptide backbone or an amino acid component replaced with a suitable mimic.
  • suitable amino acids which may be suitable amino acid mimics include ⁇ -alanine, L- ⁇ -amino butyric acid, L- ⁇ -amino butyric acid, L- ⁇ -amino isobutyric acid, L- ⁇ -amino caproic acid, 7-amino heptanoic acid, L-aspartic acid, L-glutamic acid, N- ⁇ -Boc-N- ⁇ -CBZ-L-lysine, N- ⁇ -Boc-N- ⁇ -Fmoc-L-lysine, L-methionine sulfone, L-norleucine, L-norvaline, N-
  • nucleic acids that can encode those polypeptide sequences are also disclosed. This would include all degenerate sequences related to a specific polypeptide sequence, i.e. all nucleic acids having a sequence that encodes one particular polypeptide sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the protein sequences.
  • degenerate nucleic acids encoding the disclosed variants and derivatives of the protein sequences.
  • compositions can comprise an acetyl group followed by a protecting group.
  • the protecting group can be, but is not limited to, a fatty acid.
  • the fatty acids can be saturated, unsaturated or essential fatty acids.
  • Fatty acids can include but are not limited to DHA, EPA, linoleic acid, or any other saturated amino acid such as myristic acid.
  • compositions described herein may be shown with no protecting groups, in certain embodiments (e.g., particularly for oral administration), they can bear one, two, three, four, or more protecting groups.
  • the protecting groups can be coupled to the C- and/or N-terminus of the peptide(s) and/or to one or more internal residues comprising the peptide(s) (e.g., one or more R-groups on the constituent amino acids can be blocked).
  • any of the peptides described herein can bear, e.g., an acetyl group protecting the amino terminus and/or an amide group protecting the carboxyl terminus.
  • a “dual protected peptide” is Ac-LRKLRKRLLRDWLKAFYDKVAEKLKEAF-NH 2 (SEQ ID NO:1) with blocking groups), either or both of these protecting groups can be eliminated and/or substituted with another protecting group as described herein.
  • blockage, particularly of the amino and/or carboxyl termini of the subject peptides of this invention can improve oral delivery and can also increase serum half-life.
  • protecting groups are suitable for this purpose.
  • Such groups include, but are not limited to acetyl, amide, and alkyl groups with acetyl and alkyl groups being particularly preferred for N-terminal protection and amide groups being preferred for carboxyl terminal protection.
  • the protecting groups can include, but are not limited to alkyl chains as in fatty acids, propeonyl, formyl, and others.
  • Carboxyl protecting groups include amides, esters, and ether-forming protecting groups can also be used.
  • an acetyl group can be used to protect the amino terminus and an amide group can be used to protect the carboxyl terminus.
  • Additional blocking groups include alkyl groups of various lengths, e.g., groups having the formula: CH 3 (CH 2 ) n CO where n ranges from about 1 to about 20, preferably from about 1 to about 16 or 18, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.
  • the protecting groups include, but are not limited to alkyl chains as in fatty acids, propeonyl, formyl, and others.
  • carboxyl protecting groups can include amides, esters, and ether-forming protecting groups. These blocking groups can enhance the helix-forming tendencies of the peptides.
  • Blocking groups can include alkyl groups of various lengths, e.g., groups having the formula: CH 3 (CH 2 ) n CO where n ranges from about 3 to about 20, preferably from about 3 to about 16, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.
  • protecting groups include, but are not limited to Fmoc, t-butoxycarbonyl (t-BOC), 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-florenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, Xanthyl (Xan), Trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), Benzyloxy (BzlO),
  • Protecting/blocking groups are well known to those of skill as are methods of coupling such groups to the appropriate residue(s) comprising the peptides of this invention (see, e.g., Greene et al., (1991) Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. Somerset, N.J.).
  • acetylation can be accomplished during the synthesis when the peptide is on the resin using acetic anhydride.
  • Amide protection can be achieved by the selection of a proper resin for the synthesis.
  • compositions disclosed herein can also comprise one or more D-form (dextro rather than levo) amino acids as described herein.
  • D-form amino acids Dextro rather than levo amino acids
  • at least two enantiomeric amino acids, at least 4 enantiomeric amino acids or at least 8 or 10 enantiomeric amino acids can be in the “D” form amino acids.
  • every other, or even every amino acid (e.g., every enantiomeric amino acid) of the peptides described herein is a D-form amino acid.
  • At least 50% of the enantiomeric amino acids can be “D” form, at least 80% of the enantiomeric amino acids are “D” form, at least 90%, or even all of the enantiomeric amino acids can be in the “D” form amino acids.
  • FMOC-Aha can be added to the growing chain as the last amino acid using the normal amino acid chain extension procedure (use of HOBt+DCC or HBTU as condensing agents).
  • the NH2 can be acetylated using either excess of acetic anhydride under basic conditions or by condensing acetic acid using amino acid condensing agents used for peptide chain elongation.
  • compositions comprising any of the synthetic ApoE-mimicking peptides disclosed herein and a pharmaceutically acceptable carrier.
  • a material or carrier that would be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art.
  • carriers include dimyristoylphosphatidyl (DMPC), phosphate buffered saline or a multivesicular liposome.
  • DMPC dimyristoylphosphatidyl
  • PG:PC:Cholesterol:peptide or PC:peptide can be used as carriers in this invention.
  • Other suitable pharmaceutically acceptable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A. R. Gennaro, Mack Publishing Company, Easton, Pa. 1995.
  • an appropriate amount of pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic.
  • the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution.
  • the pH of the solution can be from about 5 to about 8, or from about 7 to about 7.5.
  • Further carriers include sustained release preparations such as semi-permeable matrices of solid hydrophobic polymers containing the composition, which matrices are in the form of shaped articles, e.g., films, stents (which are implanted in vessels during an angioplasty procedure), liposomes or microparticles.
  • compositions can also include carriers, thickeners, diluents, buffers, preservatives and the like, as long as the intended activity of the polypeptide, peptide, nucleic acid, vector of the invention is not compromised.
  • Pharmaceutical compositions may also include one or more active ingredients (in addition to the composition of the invention) such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like.
  • active ingredients in addition to the composition of the invention
  • the pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated.
  • Preparations of parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
  • Formulations for optical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids, or binders may be desirable.
  • compositions may potentially be administered as a pharmaceutically acceptable acid- or base-addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mon-, di-, trialkyl and aryl amines and substituted ethanolamines.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid
  • the ApoE-mimicking peptide can be a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha.
  • the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH 2 or Ac-Aha-[R]hE18A-NH 2 .
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein the synthetic ApoE-mimicking peptide is administered as a composition comprising the synthetic ApoE-mimicking peptide and a pharmaceutically acceptable carrier.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein binding of LDL to a cell of the subject is enhanced.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein degradation of LDL by a cell of the subject is increased.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein LDL cholesterol in the subject is lowered.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein binding of VLDL to a cell of the subject is enhanced.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein degradation of VLDL by a cell of the subject is increased.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein VLDL cholesterol in the subject is lowered.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein total plasma concentration of cholesterol in the subject is lowered.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein said synthetic ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg.
  • concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range in between.
  • Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein the subject has coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, and/or congestive heart failure, or bacterial infections.
  • the ApoE-mimicking peptide can be a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha.
  • the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH 2 or Ac-Aha-[R]hE18A-NH 2 .
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein the synthetic ApoE-mimicking peptide is administered as a composition comprising the synthetic ApoE-mimicking peptide and a pharmaceutically acceptable carrier.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein binding of LDL to a cell of the subject is enhanced.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of LDL by a cell of the subject is increased.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein LDL cholesterol in the subject is lowered.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein binding of VLDL to a cell of the subject is enhanced.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein VLDL cholesterol in the subject is lowered.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein total plasma concentration of cholesterol in the subject is lowered.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein said synthetic ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg.
  • concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range in between.
  • Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein the subject has coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, and/or congestive heart failure.
  • the ApoE-mimicking peptide can be a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha.
  • the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH 2 or Ac-Aha-[R]hE18A-NH 2 .
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein the synthetic ApoE-mimicking peptide is administered as a composition comprising the synthetic ApoE-mimicking peptide and a pharmaceutically acceptable carrier.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein binding of LDL to a cell of the subject is enhanced.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of LDL by a cell of the subject is increased.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein LDL cholesterol in the subject is lowered.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein binding of VLDL to a cell of the subject is enhanced.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein VLDL cholesterol in the subject is lowered.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein total plasma concentration of cholesterol in the subject is lowered.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein said synthetic ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg.
  • concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range in between.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein the subject has coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, and/or congestive heart failure.
  • the ApoE-mimicking peptide can be a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha.
  • the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH 2 or Ac-Aha-[R]hE18A-NH 2 .
  • Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein the synthetic ApoE-mimicking peptide is administered as a composition comprising the synthetic ApoE-mimicking peptide and a pharmaceutically acceptable carrier.
  • Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein binding of LDL to a cell of the subject is enhanced.
  • Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein degradation of LDL by a cell of the subject is increased.
  • Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein LDL cholesterol in the subject is lowered.
  • Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein binding of VLDL to a cell of the subject is enhanced.
  • Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
  • Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein VLDL cholesterol in the subject is lowered.
  • Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein total plasma concentration of cholesterol in the subject is lowered.
  • Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein said synthetic ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg.
  • the concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range in between.
  • lipid disorder can be coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, and/or congestive heart failure.
  • dosing regimens comprising at least one treatment cycle of an effective amount of any of the disclosed Apo E-mimicking peptides followed by a rest phase.
  • the rest phase of the dosing regimen is a period of time where the Apo E-mimicking peptide is not administered.
  • the ApoE-mimicking peptide can be, but is not limited to, Ac-Aha-hE18A-NH 2 or Ac-Aha-[R]hE18A-NH 2 .
  • dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase.
  • an effective amount of Apo E-mimicking peptide result in sustained therapeutic effects, but it is also an amount sufficient to cause an acute beneficial effect.
  • the effects of the Apo E-mimicking peptide can be measured and seen during the treatment cycle, at the end of the treatment cycle and during the rest phase.
  • the sustained therapeutic effects are the therapeutic effects seen even after an acute cholesterol lowering effect is gone.
  • dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic, wherein the Apo E-mimicking peptide is not administered during the rest phase, wherein the treatment cycle comprises administration of an effective amount of the Apo E-mimicking peptide once a week for three months or wherein the treatment cycle comprises administration of an effective amount of the Apo E-mimicking peptide once every two weeks for up to 12 weeks.
  • dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase, wherein the dosing regimen further comprises a second treatment cycle after the rest phase.
  • dosing regimens can comprise at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha.
  • Dosing regimens can further include a second treatment cycle after the rest phase.
  • a second rest phase can occur after the second treatment cycle.
  • a third, fourth, fifth, sixth, seventh, eighth, ninth or tenth treatment cycle can be administered wherein each treatment cycle is followed by a rest phase.
  • the dosing regimen includes infinite treatment cycles, each followed by a rest phase.
  • a subject may be prescribed a dosing regimen that involves consecutive treatment cycles followed by rest phases for the duration of their life.
  • a second dosing regimen can be prescribed based on the re-occurrence of atherosclerotic lesions or other atherosclerosis factors.
  • the second dosing regimen can be administered 1, 2, 3, 4, 5 years or more than 5 years after the initial dosing regimen was administered.
  • the second dosing regimen can be the same as the initial dosing regimen or can be different.
  • the initial dosing regimen can be a three month treatment cycle followed by a one year rest phase. After the one year rest phase the subject can be tested and if atherosclerotic lesions are building up again then a second dosing regimen consisting of another three month treatment cycle followed by a rest phase or a six month treatment cycle followed by a rest phase can be prescribed.
  • the dose of Apo E mimetic can vary between the initial dosing regimen and any additionally prescribed dosing regimens.
  • the second dosing can be administered based on vasoresponsiveness, presence of isolated systolic hypertension, or exercise-induced angina determined in the subject after the first treatment.
  • the second dose can be administered based on the amount of plasma cholesterol. The frequency of administration can be altered depending on the need for reducing plasma cholesterol to minimize or eliminate the risk for any of the disorders disclosed herein.
  • Treatment cycles can include the administration of different dosages of ApoE-mimicking peptide as well as administration at different time points.
  • the ApoE-mimicking peptide can be administered for varying amounts of time for up to 6 months. In some instances, the administration can occur for up to one, two, three, four, five or six months.
  • the ApoE-mimicking peptide can be administered once a week for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks.
  • the length of time for each treatment cycle can vary depending on the amount of ApoE-mimicking peptide administered per dosage.
  • a treatment cycle can include the administration of ApoE-mimicking peptide once, twice or three times a week.
  • the ApoE-mimicking peptide can be administered daily.
  • the ApoE-mimicking peptide can be administered once every two weeks or even once a month.
  • the Apo E mimetic can be administered every two weeks for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks.
  • the treatment cycle can include administering an ApoE-mimicking peptide once a week for four weeks or once every two weeks for up to six months.
  • each treatment cycle includes an established length of time for administration as well as an established dosing schedule during that time frame.
  • more than one ApoE-mimicking peptide can be administered during the treatment cycles.
  • the more than one ApoE-mimicking peptide can be formulated together or in separate compositions.
  • one or more Apo E mimetic is administered in combination with one or more other therapeutic agents, such as cholesterol lowering drugs.
  • the disclosed dosing regimens can include at least one treatment cycle followed by a rest phase.
  • the rest phase is a period of time wherein ApoE-mimicking peptide is not administered and the length of the period of time can vary.
  • the length of the rest phase is dependent on how long the sustained therapeutic effects of the Apo E mimetic administered during the treatment cycle last.
  • the rest phase can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • the rest phase can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years.
  • the rest phase can be at least four weeks (one month).
  • One way to determine how long the rest phase should last is to test the subject to determine the progression of the atherosclerosis burden in the subject's arteries. If the atherosclerosis burden has progressed to a level that increases the risk of cardiovascular disease, then the subject can be prescribed a second dosing regimen. If the atherosclerosis burden is stable then the rest phase can be prolonged.
  • the length of the reset phase can also be based on VLDL reduction, LDL reduction, glucose reduction, inflammation reduction, vasoresponsiveness, presence of isolated systolic hypertension, or exercise-induced angina, or amount of plasma cholesterol.
  • Subjects can be tested on a regular basis. For example, a subject can be tested every 3, 6, 9, 12, 18, 24, 30 or 36 months.
  • the rest phase can be decreased or extended depending on the dose of ApoE-mimicking peptide administered and the reduction in atherosclerosis achieved during the treatment cycle.
  • the rest phase can be extended if the dose of ApoE-mimicking peptide during the treatment cycle is increased and the atherosclerosis burden is substantially reduced.
  • the length of the rest phase can also vary based on the length of the treatment cycle. For instance, if a subject receives a certain dose of ApoE-mimicking peptide once a week for three months then the rest phase may be shorter than a subject that receives the same dose of Apo E mimetic once a week for six months.
  • an atherosclerosis therapeutic other than an Apo E mimetic can be administered during the rest phase.
  • the atherosclerosis therapeutic other than an Apo E mimetic can be a conventional lipid lowering therapy, such as a statin, a bile acid sequestrant or a fibrate, or a novel anti-atherosclerosis therapeutic like a CETP inhibitor, a VLDL synthesis inhibitor, a PCSK9 inhibitor, and/or an arterial inflammation inhibitor.
  • the atherosclerosis therapeutic other than an Apo E mimetic can be a conventional LDL lowering therapeutic or a HDL elevating therapeutic.
  • the beneficial effects of the Apo E mimetic can still be present in a subject even after the treatment cycle is complete.
  • the half-life of the Apo E mimetic is less than 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 days.
  • the Apo E mimetic is no longer detectable in a subject after the treatment cycle is complete. Thus, the long-term therapeutic effects are not from residual Apo E mimetic.
  • the dose or dosage of ApoE-mimicking peptide can vary depending on many factors, such as but not limited to, age, condition, sex and extent of the disease in the patient, route of administration, length of treatment cycle, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.
  • Effective dosages can be determined empirically, and making such determinations is within the skill in the art.
  • the dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the disease is treated.
  • the dosage can be an amount effective to provide therapeutic effects and provide or allow for sustained therapeutic effects even after the treatment (i.e. ApoE-mimicking peptide) is withdrawn.
  • the therapeutic effects can be, but are not limited to, a reduction in atherosclerotic lesions, decrease in arterial stiffness, decrease in isolated systolic hypertension, increase in vasoresponsiveness or improvement in cardiac function.
  • the therapeutic effects can be measured by markers of arterial inflammation such as, but not limited to, C-reactive protein.
  • the therapeutic effects can be measured by atherosclerosis imaging techniques, including MRI, intravascular ultrasound, ultrafast imaging CT scans, B-mode ultrasonography, virtual histology intravascular ultrasound, optical coherence tomography, or other known methods.
  • the dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like.
  • the dosage can be adjusted by the individual physician in the event of any counter-indications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • Suitable dosages include, but are not limited to amounts between 0.01 mg/kg and 20 mg/kg.
  • disclosed herein are methods involving administering one or more of the disclosed ApoE-mimicking peptide to a subject, wherein the ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg.
  • the concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg.
  • the ApoE-mimicking peptide dose can be administered as a bolus injection or as an infusion over one or more hours.
  • Methods of treating acute coronary syndrome (ACS) or atherosclerosis comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle followed by a rest phase are provided.
  • the Apo E-mimicking peptide can be Ac-Aha-hE18A-NH 2 or Ac-Aha-[R]hE18A-NH 2 .
  • the disclosed methods involve administering an Apo E-mimicking peptide using one or more of the disclosed dosing regimens.
  • any of the disclosed treatment cycles or rest phases can be used in the disclosed methods.
  • the methods disclosed herein can allow for prolonged therapeutic effects even in the absence of the therapeutic.
  • the disclosed methods can include the administration of an effective amount of Apo E mimetic.
  • the effective amount of an Apo E mimetic can be an amount that allows for sustained therapeutic effects after the Apo E mimetic has been withdrawn.
  • Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase.
  • Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase, wherein the rest phase is at least four weeks.
  • Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase.
  • the second treatment cycle can be administered after a four week rest phase or one year from the beginning of the initial treatment cycle.
  • Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase, wherein an ACS therapeutic other than an Apo E-mimicking peptide is administered during the rest phase.
  • the ACS therapeutic other than an Apo E-mimicking peptide can be a conventional LDL lowering therapy or HDL elevating therapy.
  • a conventional LDL lowering therapy can be, but is not limited to, a statin.
  • An HDL elevating therapy can be, but is not limited to, Apo A1 elevating drug, a CETP inhibitor, a phospholipase A2 inhibitor, an Apo A1 Milano, or an Apo A1 mimetic.
  • Atherosclerosis comprising administering to a subject an effective amount of an Apo E mimetic for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E mimetic to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic, wherein the Apo E mimetic consists of the Ac-Aha-hE18A-NH 2 or Ac-Aha-[R]hE18A-NH 2 peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E mimetic is not administered during the rest phase.
  • Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase, wherein the treatment cycle comprises administration of an effective amount of an Apo E-mimicking peptide once a week for three months.
  • the disclosed methods of treating can occur at different times depending on the subject.
  • treatment can occur in a subject considered to be of high, or high residual risk of a cardio- or cerebrovascular event.
  • the treatment can be initiated after a subject is stabilized following an acute coronary event.
  • the treatment can be initiated immediately after the acute coronary event, or 3, 6, 9, or 12 months after the acute coronary event.
  • the treatment can be initiated following acute interventional cardiology procedures such as coronary artery bypass surgery (CABG), percutaneous coronary intervention (angioplasty, PCI), or implant of a stent into a coronary artery.
  • Subjects considered as high risk can be those individuals that have homozygous familial hypercholesterolemia (FH), severe refractory FH, diabetes or an individual following acute coronary syndrome (ACS). In high risk subjects, treatment can be extended.
  • the treatment cycle can vary in length of time.
  • the treatment cycle can be at least four weeks but can last up to six months.
  • the disclosed methods have a treatment cycle that involves the administration of an effective amount of an ApoE-mimicking peptide once a week for one month (four weeks), three months (12 weeks) or six months (24 weeks).
  • a treatment cycle can include the administration of ApoE-mimicking peptide once, twice or three times a week.
  • the ApoE-mimicking peptide can be administered daily.
  • the ApoE-mimicking peptide can be administered once every two weeks or even once a month.
  • the ApoE-mimicking peptide can be administered every two weeks for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks.
  • Each treatment cycle can include an established length of time for administration as well as an established dosing schedule during that time frame.
  • the methods can further include a second treatment cycle after the rest phase.
  • the second treatment cycle can be administered after a four week rest phase.
  • the second treatment cycle can be administered at least one year from the beginning of the initial treatment cycle.
  • the rest phase as previously described with regards to the dosing regimen, can be at least four weeks but can last for several years.
  • the ApoE-mimicking peptide is not administered during the rest phase.
  • the length of the rest phase is dependent on how long the sustained therapeutic effects of the ApoE-mimicking peptide administered during the treatment cycle last.
  • the rest phase can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • the rest phase can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years.
  • the rest phase can be at least four weeks (one month).
  • the rest phase can be decreased or extended depending on the dose of ApoE-mimicking peptide administered during the treatment cycle.
  • the rest phase can be extended if the dose of ApoE-mimicking peptide during the treatment cycle is increased.
  • the length of the rest phase can also vary based on the length of the treatment cycle. For instance, if a subject receives a certain dose of ApoE-mimicking peptide once a week for three months then the rest phase may be shorter than a subject that receives the same dose of ApoE-mimicking peptide once a week for six months.
  • an atherosclerosis therapeutic other than an ApoE-mimicking peptide can be administered during the rest phase.
  • the atherosclerosis therapeutic other than an Apo E mimetic can be a conventional lipid lowering therapy, such as a statin, or bile acid sequestrant, and/or a therapeutic such as a PCSK9 inhibitor, a VLDL synthesis inhibitor and/or a CETP inhibitor.
  • the combination of LDL accumulation in a vessel wall and an inflammatory response to the LDL's is responsible for initiating atherosclerosis.
  • the LDL within the vessel wall becomes oxidized which damages the vessel wall and triggers an immune response.
  • Immune cells such as macrophages, are not able to process the oxidized-LDL and eventually rupture which leads to more oxidized cholesterol in the artery wall. This cycle continues which causes more and more damage to the vessel walls.
  • the increase in cholesterol leads to plaques which ultimately results in hardening and narrowing of the vessel wall.
  • the disclosed methods are useful for treating atherosclerosis and other lipid disorders.
  • administration or delivery of the ApoE-mimicking peptides can be via a variety of mechanisms.
  • disclosed herein are methods of treating, dosing regimens and methods of using those dosing regimens to treat.
  • the dosing regimens and methods include compositions containing any one or more of the polypeptides or nucleic acids described herein that can also include a carrier such as a pharmaceutically acceptable carrier.
  • a carrier such as a pharmaceutically acceptable carrier.
  • pharmaceutical compositions comprising the ApoE-mimicking peptide disclosed herein, and a pharmaceutically acceptable carrier.
  • the disclosed ApoE-mimicking peptide can be in solution or in suspension (for example, incorporated into microparticles, liposomes, or cells). These compositions can be targeted to a particular cell type via antibodies, receptors, or receptor ligands.
  • a targeting agent can be a vehicle such as an antibody conjugated liposomes; receptor mediated targeting of DNA through cell specific ligands, and highly specific retroviral targeting of cells in vivo. Any such vehicles can be part of the compositions herein.
  • targeting agents that direct the ApoE-mimicking peptide to the blood vessel walls can be included in the compositions.
  • Suitable routes of administration can be used for the disclosed compositions.
  • Suitable routes of administration can, for example, include topical, enteral, local, systemic, or parenteral.
  • administration can be epicutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular, intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavernosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracisternal, epidural, peridural, intravitreal, etc.
  • the disclosed compositions can be used in and with any other therapy.
  • the peptides of this invention comprising D-form amino acids can be administered, even orally, without protection against proteolysis by stomach acid, etc.
  • peptide delivery can be enhanced by the use of protective excipients. This is typically accomplished either by complexing the polypeptide with a composition to render it resistant to acidic and enzymatic hydrolysis or by packaging the polypeptide in an appropriately resistant carrier such as a liposome.
  • protective excipients This is typically accomplished either by complexing the polypeptide with a composition to render it resistant to acidic and enzymatic hydrolysis or by packaging the polypeptide in an appropriately resistant carrier such as a liposome.
  • Means of protecting polypeptides for oral delivery are well known in the art (see, e.g., U.S. Pat. No. 5,391,377 describing lipid compositions for oral delivery of therapeutic agents).
  • Elevated serum half-life can be maintained by the use of sustained-release protein “packaging” systems.
  • sustained release systems are well known to those of skill in the art.
  • the ProLease biodegradable microsphere delivery system for proteins and peptides (Tracy (1998) Biotechnol. Prog., 14: 108; Johnson et al. (1996) Nature Med. 2: 795; Herbert et al. (1998), Pharmaceut. Res. 15, 357) a dry powder composed of biodegradable polymeric microspheres containing the active agent in a polymer matrix that can be compounded as a dry formulation with or without other agents.
  • the ProLease microsphere fabrication process was specifically designed to achieve a high encapsulation efficiency while maintaining integrity of the active agent.
  • the process consists of (i) preparation of freeze-dried drug particles from bulk by spray freeze-drying the drug solution with stabilizing excipients, (ii) preparation of a drug-polymer suspension followed by sonication or homogenization to reduce the drug particle size, (iii) production of frozen drug-polymer microspheres by atomization into liquid nitrogen, (iv) extraction of the polymer solvent with ethanol, and (v) filtration and vacuum drying to produce the final dry-powder product.
  • the resulting powder contains the solid form of the active agents, which is homogeneously and rigidly dispersed within porous polymer particles.
  • the polymer most commonly used in the process poly(lactide-co-glycolide) (PLG), is both biocompatible and biodegradable.
  • Encapsulation can be achieved at low temperatures (e.g., ⁇ 40° C.). During encapsulation, the protein is maintained in the solid state in the absence of water, thus minimizing water-induced conformational mobility of the protein, preventing protein degradation reactions that include water as a reactant, and avoiding organic-aqueous interfaces where proteins may undergo denaturation.
  • a preferred process uses solvents in which most proteins are insoluble, thus yielding high encapsulation efficiencies (e.g., greater than 95%).
  • one or more components of the solution can be provided as a “concentrate”, e.g., in a storage container (e.g., in a premeasured volume) ready for dilution, or in a soluble capsule ready for addition to a volume of water.
  • the Apo E mimetics can be administered alone or in combination with one or more additional therapeutic agents.
  • the additional therapeutic agents are selected based on the disease or symptom to be treated.
  • a description of the various classes of suitable pharmacological agents and drugs may be found in Goodman and Gilman, The Pharmacological Basis of Therapeutics, (11th Ed., McGraw-Hill Publishing Co.) (2005).
  • pharmaceutical compositions containing Apo E mimetics can be administered in combination with one or more known therapeutic agents for treating atherosclerosis.
  • Therapeutic agents for treating atherosclerosis include, but are not limited to, cholesterol-lowering agents, HDL elevating agents, blood pressure-lowering agents, blood thinning agents (i.e.
  • cholesterol-lowering agents include, but are not limited to, a cholesterol absorption inhibitor, a bile acid sequestrant, a fibrate, a PCSK9 inhibitor, a microsomal triglyceride transfer protein inhibitor, an apolipoprotein B synthesis inhibitor, or a CETP inhibitor.
  • the Apo E mimetics can be administered in conjunction with or followed by any of the disclosed additional therapeutics.
  • the treatments can be administered in conjunction with or followed by LDL apheresis.
  • the combination therapies can include administering the Apo E mimetic and an additional therapeutic agent during the treatment cycle of a dosing regimen.
  • the combination therapies can also include administering the Apo E mimetic during the treatment cycle and an additional therapeutic agent during the rest phase.
  • the synthetic ApoE-mimicking peptides used in the studies described in FIGS. 3 - 14 were prepared were prepared by standard Fmoc solid-phase peptide synthesis techniques. Various peptides and the rationale for preparation are shown in FIG. 1 . Representative analytical HPLC profiles of the synthesized peptides are shown in FIGS. 2 A- 2 G .
  • FIGS. 3 - 14 Studies showing the effects of various synthetic ApoE-mimicking peptides on plasma cholesterol levels are shown in FIGS. 3 - 14 .
  • the peptides administered were as follows: Ac-hE18A-NH 2 , Ac—[R]hE18A-NH 2 and Ac-Aha-[R]hE18A-NH 2 where hE refers to LRKLRKRLLR (SEQ ID NO:4) and [R]hE refers to LRRLRRRLLR (SEQ ID NO:6) and Aha refers to H 2 N—(CH 2 ) 5 —COOH.
  • Blood was drawn at the times indicated in graphs and after separating cells, plasma was analyzed for cholesterol, triglycerides and glucose levels. Plasma triglycerid levels at different time points are shown in FIG. 16 . Data were also obtained at 48 h post-administration of the peptide for plasma triglyceride ( FIG. 17 ), cholesterol levels ( FIG. 18 ), and plasma glucose levels ( FIG. 19 ).
  • octanoyl-LRRLRRRLLR-18A-NH 2 (SEQ ID NO:625); (2) myristoyl-LRRLRRRLLR-18A-NH 2 (SEQ ID NO:628); (3) oleoyl-LRRLRRRLLR-18A-NH 2 (SEQ ID NO:634); (4) palmitoyl-LRRLRRRLLR-18A-NH 2 (SEQ ID NO:629); and (5) Fish oil-LRRLRRRLLR-18A-NH 2 (SEQ ID NO:647), in which fish oil was principally a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with other components in small amounts.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • the peptides were synthesized on a Rink amide resin (5 mM of the functional group present on 10 g of the resin was used). Suitable FMOC-amino acid derivatives were added using HBTu method of condensation (three couplings for each amino acid at 5 ⁇ , 3 ⁇ , and 2 ⁇ for three couplings). After the last amino acid leucine (L) was added, the resin weighed approximately 40 g, indicating quantitative yield for the coupling of amino acids. Resin (2 g) was taken for each fatty acid and each fatty acid was added two times with 10 ⁇ and 5 ⁇ couplings using HBTu in DMF.
  • the peptide was released from the resin using TFA:water:anisole:ethylenedithiol (95:2:2:1 by volume, 10 ml/G of the reagent) for 3.5 hr at room temperature. After filtration of the resin, the peptide was precipitated by adding ether, washed by centrifugation with ether three times. Peptide was first dialyzed and then purified by HPLC. Since fish oil derivative is known to contain mixture that was very difficult to purify, this was not purified but the ability of this peptide to reduce plasma cholesterol in apoE null mice was compared with other dialyzed peptides. Purification of peptides was achieved using C18 silica gel column, and FIGS. 20 A- 20 E shows representative analytical HPLC profiles of the peptides (C-18 Vydac column-250 ⁇ 4.6 mm; solvent system was a gradient of water/acetonitrile (0.1% TFA), 35-70% in 12 minutes).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

Disclosed are synthetic apolipoprotein E-mimicking peptides, derivatives thereof, and related peptides, which are useful as therapeutic agents for reducing plasma cholesterol; synthetic methods of making the peptides; pharmaceutical compositions comprising the peptides, and methods of treating lipid and metabolic disorders using the disclosed synthetic apolipoprotein E-mimicking peptides and compositions thereof. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

CROSS REFERENCE TO RELATED APPLICATIONS
This application is a reissue of U.S. Pat. No. 10,653,747, issued May 19, 2020, which is a national phase filing of International Patent Application No. PCT/US2015/041162, filed Jul. 20, 2015, which claims priority to U.S. Application No. 62/031,585, filed Jul. 31, 2014, both of which are herein incorporated by reference in their entireties.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
This invention was made with government support under RO1 HL 090803 awarded by the National Institutes of Health. The government has certain rights in the invention.
REFERENCE TO A SEQUENCE LISTING SUBMITTED AS A TEXT FILE VIA EFS-WEB
The Sequence Listing submitted Aug. 21, 2018 as a text file named “21085_0187U2_Updated_Sequence_Listing.txt,” created on Aug. 14, 2018 Aug. 6, 2024, as a text file named “21085.0187U3 Sequence Listing.txt” created on Aug. 6, 2024, and having a size 311,540 311,533 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5).
BACKGROUND
In the United States, heart disease is the leading cause of death in both men and women. Several causative factors are implicated in the development of cardiovascular disease including hereditary predisposition to the disease, gender, lifestyle factors such as smoking and diet, age, hypertension, and hyperlipidemia, including hypercholesterolemia. Several of these factors, particularly hyperlipidemia and hypercholesteremia (high blood cholesterol concentrations) provide a significant risk factor associated with atherosclerosis.
Atherosclerosis is associated with an inflammatory response caused by the accumulation of low-density lipoprotein (LDL) molecules in blood vessels. It can be asymptomatic for years. Atherosclerosis causes hardening and narrowing of blood vessels. There are several treatments for atherosclerosis, such as lifestyle change, medication and medical procedures. Statins are a well-known treatment for atherosclerosis. Statins have proven to reduce cardiac risk however the withdrawal of statin therapy abrogrates the protective effect (Heeschen et al. Circulation. 105:1446-1452, 2002).
The current approach to treating atherosclerosis is to provide earlier intervention and life-long treatment. This approach is problematic as it requires identifying asymptomatic patients early in their life cycle and, since risk increases with age, maintaining therapy for the duration of their life. Further, the most efficacious currently available therapies are unable to prevent major cardiac events in all patients whether as primary or secondary interventions. Therefore, there is a need for therapies that can provide rapid benefit in reducing atherosclerosis and have long-term effects that do not require constant administration. The compositions and methods disclosed herein provide an atherosclerosis therapy with sustained therapeutic effects even after the treatment is withdrawn.
BRIEF SUMMARY
Disclosed are synthetic apolipoprotein E (ApoE)-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an acetylated amino hexanoic acid (Ac-Aha).
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the Ac-Aha can be at the N-terminus of the peptide.
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain. For example, the class A amphipathic-helical domain can be DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein said apolipoprotein E is from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein said synthetic peptide is protected using an amide group at the C-terminus.
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of ApoE is LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), or RLTRKRGLK (SEQ ID NO:13).
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of ApoE is LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), RLTRKRGLK (SEQ ID NO:13), LRRMRRRLMR (SEQ ID NO:621), or RLTRRRGK (SEQ ID NO:622).
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an acetylated ω-amino fatty acid moiety, wherein the acetylated ω-amino fatty acid moiety is at the N-terminus of the peptide. In some aspects the ω-amino fatty acid moiety can be inserted between the lipid-associating peptide and the receptor binding domain of apoE.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain. For example, the class A amphipathic-helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein said apolipoprotein E can be from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein said synthetic peptide is protected using an amide group at the C-terminus.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), or RLTRKRGLK (SEQ ID NO:13). The receptor binding domain of ApoE can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO:12), LRKLPKRLLR (SEQ ID NO:8), LRNVRKRLVR (SEQ ID NO:9), MRKLRKRVLR (SEQ ID NO:10), LRRLRRRLLR (SEQ ID NO:11), LRKLRKRFFR (SEQ ID NO:12), LRKLRKRLLR (SEQ ID NO:4), or LRKMRKRLMR (SEQ ID NO:7).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), RLTRKRGLK (SEQ ID NO:13), LRRMRRRLMR (SEQ ID NO:621), or RLTRRRGK (SEQ ID NO:22).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the synthetic ApoE-mimicking peptide can be: butanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 623); hexanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 624); octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625); decanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 626); lauroyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 627); myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628); palmitoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 629); stearoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 630); palmitoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 631); arachidoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 632); behenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 633); oleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 634); ricinoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 635); linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 636); vacceoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 637); gadoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 638); erucoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 639); cetoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 640); nervonoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 641); adrenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 642); α-linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 643); γ-linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 644); EPA-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 645); or DHA-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 646). In the foregoing, the fatty acid moiety is shown at the left side and is linked to the peptide LRRLRRRLLR (SEQ ID NO:11). “EPA” indicates a moiety derived from 5,8,11,14,17-eicosapentaenoic acid; and “DHA” indicates a moiety derived from 4,7,10,13,16,19-docosahexaenoic acid.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety derived from a natural oil or fat, e.g. fish oil, wherein the synthetic ApoE-mimicking peptide can be: (fish oil)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 647). In the foregoing “(fish oil)” indicates that the fatty acids in fish oil, including, but not limited to, fish oil components such as EPA and DHA, are linked to linked to the peptide LRRLRRRLLR (SEQ ID NO:11). Thus, the synthetic ApoE-mimicking peptide is a mixture of peptides comprising fatty acid groups derived from the fish oil used to prepare them.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the synthetic ApoE-mimicking peptide can be: 4-amino-butanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 648); 6-amino-hexanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 649); 8-amino-octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 650); 10-amino-decanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 651); 12-amino-lauroyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 652); 14-amino-myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 653); 16-amino-palmitoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 654); 16-amino-palmitoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 655); 18-amino-stearoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 656); 18-amino-oleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 657); 18-amino-linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 658); or 20-amino-arachidoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 659). In the foregoing, the fatty acid moiety is shown at the left side and is linked to the peptide LRRLRRRLLR (SEQ ID NO:11).
Disclosed are pharmaceutical compositions comprising any one of the herein disclosed synthetic ApoE-mimicking peptides and a pharmaceutically acceptable carrier.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein the synthetic apolipoprotein E-mimicking peptide is administered as a composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein binding of LDL to a cell of the subject is enhanced.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein degradation of LDL by a cell of the subject is increased.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein LDL cholesterol in the subject is lowered.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein binding of VLDL to a cell of the subject is enhanced.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein degradation of VLDL by a cell of the subject is increased.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein VLDL cholesterol in the subject is lowered.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein total plasma concentration of cholesterol in the subject is lowered.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein said synthetic apolipoprotein E-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein the subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, peripheral artery disease (PAD), cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
Also disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein the synthetic apolipoprotein E-mimicking peptide is administered as a composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein binding of LDL to a cell of the subject is enhanced.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein degradation of LDL by a cell of the subject is increased.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein LDL cholesterol in the subject is lowered.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein binding of VLDL to a cell of the subject is enhanced.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein VLDL cholesterol in the subject is lowered.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein total plasma concentration of cholesterol in the subject is lowered.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein said synthetic apolipoprotein E-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein the subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
Also disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein the synthetic apolipoprotein E-mimicking peptide is administered as a composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein binding of LDL to a cell of the subject is enhanced.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein degradation of LDL by a cell of the subject is increased.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein LDL cholesterol in the subject is lowered.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein binding of VLDL to a cell of the subject is enhanced.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein VLDL cholesterol in the subject is lowered.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein total plasma concentration of cholesterol in the subject is lowered.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein said synthetic apolipoprotein E-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic apolipoprotein E-mimicking peptides, wherein the subject has coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
Also disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein the synthetic apolipoprotein E-mimicking peptide is administered as a composition comprising the synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein binding of LDL to a cell of the subject is enhanced.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein degradation of LDL by a cell of the subject is increased.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein LDL cholesterol in the subject is lowered.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein binding of VLDL to a cell of the subject is enhanced.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein degradation of VLDL by a cell of the subject is increased.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein VLDL cholesterol in the subject is lowered.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein total plasma concentration of cholesterol in the subject is lowered.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein said synthetic apolipoprotein E-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 12 mg/kg.
Disclosed are methods for treating a subject with a Lipid Disorder, the method comprising administering to the subject an effective amount of any one of the disclosed synthetic apolipoprotein E-mimicking peptides, or a composition thereof, wherein the lipid disorder is coronary artery disease, rheumatoid arthritis, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, congestive heart failure, and/or systemic lupus.
Also disclosed are dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of any of the disclosed Apo E-mimicking peptides to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase. In some instances, the treatment cycle comprises administration of an effective amount of the Apo E-mimicking peptide once a week for three months. In some instances, the treatment cycle comprises administration of an effective amount of the Apo E-mimicking peptide once every two weeks for up to 12 weeks.
Disclosed are dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of any of the disclosed Apo E-mimicking peptides to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase, wherein the dosing regimen further comprises a second treatment cycle after the rest phase.
Also disclosed are methods of treating acute coronary syndrome (ACS) comprising administering to a subject an effective amount of any of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase.
Disclosed are methods of treating acute coronary syndrome (ACS) comprising administering to a subject an effective amount of any of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, wherein the rest phase is at least four weeks.
Disclosed are methods of treating acute coronary syndrome (ACS) comprising administering to a subject an effective amount of any of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase. In some instances, the second treatment cycle can be administered after a four week rest phase. In some instances, the second treatment cycle can be administered one year from the beginning of the initial treatment cycle.
Disclosed are methods of treating acute coronary syndrome (ACS) comprising administering to a subject an effective amount of any of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase, wherein an ACS therapeutic other than an Apo E-mimicking peptide is administered during the rest phase.
Disclosed are methods of treating acute coronary syndrome (ACS) comprising administering to a subject an effective amount of any of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase, wherein an ACS therapeutic other than an Apo E-mimicking peptide is administered during the rest phase, wherein the ACS therapeutic other than an Apo E-mimicking peptide is a conventional LDL lowering therapy or HDL elevating therapy. In some instances, the conventional LDL lowering therapy can be a statin. In some instances, the HDL elevating therapy can be an Apo A1 elevating drug, a CETP inhibitor, a phospholipase A2 inhibitor, an Apo A1 Milano, or an Apo A1 mimetic.
Disclosed are methods of treating acute coronary syndrome (ACS) comprising administering to a subject an effective amount of any of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E-mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase, wherein an ACS therapeutic other than an Apo E-mimicking peptide is administered during the rest phase, wherein the ACS therapeutic other than an Apo E-mimicking peptide is a conventional LDL lowering therapy or HDL elevating therapy, wherein the treatment cycle comprises administration of an effective amount of an Apo E-mimicking peptide once a week for three months.
Also disclosed are monoclonal antibodies that specifically bind to any one of the disclosed synthetic ApoE peptides.
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-AHA, wherein the receptor binding domain of apolipoprotein E is scrambled.
Also disclosed are synthetic apolipoprotein E-mimicking peptides consisting of a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein receptor binding domain is covalently linked to said lipid-associating peptide, wherein both the receptor binding domain of apolipoprotein E and the lipid-associating peptide are scrambled.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosed method and compositions and together with the description, serve to explain the principles of the disclosed method and compositions.
FIG. 1 describes several strategies used to develop a highly effective peptide. From top to bottom in the “Sequence” column, the sequences are as follows: SEQ ID NO:664, 665, 666, 667, 668, 669, 670, 662, 671, 672, 673, 674.
FIGS. 2A-2G shows the comparative analytical HPLC profiles of the indicated ApoE mimetic peptide analogs. Chromatography was carried out as follows: C-18 column-250×4.6 mm; mobile phase was a gradient of 30-70% acetonitrile in water over 35 minutes (with 0.1% TFA).
FIG. 3 shows cholesterol reduction (percent reduction in plasma cholesterol) by the indicated apoE mimetic peptide analogs in apoE null Mice (100 μg/mouse) following a single dose administration (n=4 animals/group). The baseline level is the relative plasma cholesterol level at the time of dose administration. The time points show the plasma cholesterol levels at the indicated times following a single dose administration. A single dose was administered using a saline vehicle.
FIG. 4 shows the comparative analytical HPLC profiles of three active ApoE mimetic peptide analogs. Chromatography was carried out as follows: C-18 column-250×4.6 mm; mobile phase was a gradient of 30-70% acetonitrile in water over 12 minutes (with 0.1% TFA).
FIGS. 5A-5B shows representative data for the effect of three active ApoE mimetic peptide analogs in reducing plasma cholesterol (% reduction) at a dose level was either 50 μg (FIG. 5A) or a dose level was either 100 μg (FIG. 5B). The study was carried out in apoE null mice (n=4 animals/group). The time points show the plasma cholesterol levels at the indicated times following a single dose administration. A single dose was administered using a saline vehicle. The data show that AC-Aha-[R]hE18A-NH2 is highly effective in reducing plasma cholesterol in ApoE-null mice at both 50 and 100 μg/mouse.
FIG. 6 shows a model for CH3—(CH2)n—CO-(apoE mimetic peptide) molecules to more avidly attach to a lipid particle than an apoE mimetic peptide that does not comprise an alkyl carboxyl moiety, and thus provides a model for enhanced hepatic clearance.
FIG. 7 is a table showing experimental design. ApoE-null mice were dosed with the peptides Ac-he18A-NH2 (AEM-28), Ac—[R]he18A-NH2 (AEM-28(R)), or Ac-Aha-[R]he18A-NH2 (AES-21), in saline via tail vein injection at a concentration of 100 ug/mouse. Blood was collected via a cheek bleed at pre-dose, and at 1, 6 and 24 hours post dose. Serum samples can be analyzed for total serum cholesterol (using Waco total cholesterol kit).
FIGS. 8A and 8B are graphs showing total cholesterol (mg/dL) versus time (FIG. 8A) and total cholesterol (% of pre-dose) versus time (FIG. 8B), respectively. Three different peptides were administered via tail vein injections into female apoE null mice, approximately 10 wks of age, using 100 ug of peptide in saline. Error bars shown are standard error of the mean (SEM). All results (n=5 animals) except Group 1 (n=4 animals all timepoints).
FIG. 9 is a table showing the results from the mouse injections described in FIG. 8 .
FIG. 10 is a table showing the results of total serum cholesterol (as % of pre-dose level).
FIG. 11 shows an experimental design. ApoE-null mice were dosed with AC-hE18A-NH2 (AEM-28), AC-[R]hE18A-NH2 (AEM-28(R)), or AC-Aha-[R]he18A-NH2 (AES2-21), in saline via tail vein injection at a concentration of 50 μg/mouse. Blood was collected via a cheek bleed at pre-dose, and at 1, 6 and 24 hours post dose. Serum samples will be analyzed for total serum cholesterol (using a total cholesterol kit (Wako Chemicals USA, Inc., Richmond, Va.)).
FIGS. 12A and 12B are graphs showing total cholesterol (mg/dL) vs time and total cholesterol (% of pre-dose) vs time, respectively. Three different peptides were administered via tail vein injections into female ApoE KO mice, approximately 10 wks of age, using 100 ug of peptide in saline. Animals were allowed to recover for 2 weeks prior to second dosing with 50 μg of peptide in saline. Error bars shown are standard error of the mean (SEM). All results (n=5 animals). “AEM-28 saline” indicates the peptide AC-hE18A-NH2; “AEM-28(R) saline” indicates the peptide AC-[R]hE18A-NH2; and “AES2-21” indicates the peptide AC-Aha-[R]he18A-NH2.
FIG. 13 is a table showing raw cholesterol values.
FIG. 14 is a table showing % of pre-dose cholesterol.
FIG. 15 shows representative data for the plasma triglyceride profile in a sucrose-fed rat model. The data show that following two weeks of a diet containing 65% (w/v) sucrose there was an increase in triglyceride levels. The study was carried out in male Sprague-Dawley rats.
FIG. 16 show representative data for the effect of disclosed synthetic apolipoprotein E-mimicking peptides on triglyceride levels in rats fed a high sucrose (65% (w/v)) diet for two weeks at the indicated times post-administration of the indicated peptide (in saline vehicle) or control (saline) via a single dose (via intravenous tail vein injection). “Control” indicates rats administered administered saline; “AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac-hE18A-NH2; “R-AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac—[R]hE18A-NH2; and “Aha-R-AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Aha-[R]hE18A-NH2.
FIG. 17 show representative data for the effect of disclosed synthetic apolipoprotein E-mimicking peptides on triglyceride levels in rats fed a high sucrose (65% (w/v)) diet for two weeks at 48 h post-dosing with the indicated peptide or control (saline). “Saline” indicates rats administered administered (i.v. via tail vein) saline; “AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac-hE18A-NH2; “R-AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac—[R]hE18A-NH2; and “Aha-R-AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Aha-[R]hE18A-NH2.
FIG. 18 show representative data for the effect of disclosed synthetic apolipoprotein E-mimicking peptides on plasm cholesterol levels in rats fed a high sucrose (65% (w/v)) diet for two weeks at 48 h post-dosing with the indicated peptide or control (saline). “Saline” indicates rats administered administered (i.v. via tail vein) saline; “AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac-hE18A-NH2; “R-AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac—[R]hE18A-NH2; and “Aha-R-AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Aha-[R]hE18A-NH2.
FIG. 19 show representative data for the effect of disclosed synthetic apolipoprotein E-mimicking peptides on plasma glucose levels in rats at 48 h post-dosing with the indicated peptide (in saline vehicle) or control (saline). The rats had been fed a high sucrose (65% (w/v)) diet for two weeks prior to peptide injection. “Saline” indicates rats administered administered (i.v. via tail vein) saline; “AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac-hE18A-NH2; “R-AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Ac—[R]hE18A-NH2; and “Aha-R-AEM-28” indicates rats administered (i.v. via tail vein) 5 mg/kg of the peptide Aha-[R]hE18A-NH2.
FIGS. 20A-20E shows representative analytical HPLC profiles for the indicated disclosed synthetic apolipoprotein E-mimicking peptides comprising a fatty acid moiety. Chromatography was carried out as follows: C-18 Vydac column-250×4.6 mm; mobile phase was a gradient of water/acetonitrile (0.1% TFA), 35-70% in 12 minutes.
FIG. 21 shows representative data for the effect of for disclosed synthetic apolipoprotein E-mimicking peptides comprising a fatty acid moiety on plasma cholesterol levels (% reduction in plasma cholesterol). The data were obtained using apoE null mice (female; group=4) administered 100 μg of the indicated peptide (in saline vehicle) at the indicated times post-administration of the peptide. The peptides administered in this study were dialyzed following synthesis without further HPLC purification. Baseline levels are the plasma cholesterol levels at the time of peptide administration. All peptides were administered via intravenous tail vein injection.
FIG. 22 shows representative data for the effect of for disclosed synthetic apolipoprotein E-mimicking peptides comprising a fatty acid moiety on plasma cholesterol levels. The data were obtained using apoE null mice (female; group=3) administered 50 μg of the indicated peptide. The study was otherwise carried out as described for FIG. 21 . The indicated times are the times post-administration of a single 50 μg dose via intravenous tail vein injection.
FIG. 23 shows representative data for the effect of for disclosed synthetic apolipoprotein E-mimicking peptides comprising a fatty acid moiety on plasma cholesterol levels. The data were obtained using apoE null mice (female; group=3) administered 100 μg of the indicated peptide. The study was otherwise carried out as described for FIG. 21 . The indicated times are the times post-administration of a single 50 μg dose via intravenous tail vein injection.
FIG. 24 show representative dose response data for the effect of myristoyl-LRRLRRRLLR-18A-NH2 (i.e., myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628)) on plasma cholesterol levels. The data were obtained using apoE null mice (female; group=5) administered the indicated dose levels. Samples were collected at 24 hr post-administration of the peptide. The study was otherwise carried out as described for FIG. 21 . The indicated doses were administered via intravenous tail vein injection.
FIG. 25 show representative dose response data for the effect of myristoyl-LRRLRRRLLR-18A-NH2 (i.e., myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628)) on plasma cholesterol levels. The data were obtained using apoE null mice (female; group=5) administered the indicated dose levels. Samples were collected at the indicated times post-administration of the peptide. The study was otherwise carried out as described for FIG. 21 . The indicated doses were administered via intravenous tail vein injection.
FIG. 26 shows data from the study described for FIG. 25 replotted in terms of maximum percent decrease in plasma cholesterol (at 5 hr) versus dose level (μg). The data are show as closed circles with the line the result of a hyperbolic curve fit to the data.
FIG. 27 shows data from the study described for FIG. 25 replotted in terms of the percent decrease in plasma cholesterol at 24 hr versus dose level (μg). The data are show as closed circles with the line the result of a hyperbolic curve fit to the data.
FIG. 28 show representative dose response data for the effect of octanoyl-LRRLRRRLLR-18A-NH2 (i.e., octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625)) on plasma cholesterol levels (mg/dL). The data were obtained using apoE null mice (female; group=5) administered the indicated dose levels. Samples were collected at the indicated times post-administration of the peptide. The study was otherwise carried out as described for FIG. 21 . The indicated doses were administered via intravenous tail vein injection.
FIG. 29 show representative dose response data for the effect of octanoyl-LRRLRRRLLR-18A-NH2 (i.e., octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625)) on plasma cholesterol levels (percent of baseline plasma cholesterol levels). The baseline level is the plasma cholesterol level at the time of the peptide administration. The data were obtained using apoE null mice (female; group=5) administered the indicated dose levels. Samples were collected at the indicated times post-administration of the peptide. The study was otherwise carried out as described for FIG. 21 . The indicated doses were administered via intravenous tail vein injection.
FIG. 30 shows data from the study described for FIGS. 28-29 replotted in terms of maximum percent decrease in plasma cholesterol (at 5 hr) versus dose level (μg). The data are show as closed circles with the line the result of a hyperbolic curve fit to the data.
FIG. 31 shows data from the study described for FIGS. 28-29 replotted in terms of the percent decrease in plasma cholesterol at 24 hr versus dose level (μg). The data are show as closed circles with the line the result of a hyperbolic curve fit to the data.
 DETAILED DESCRIPTION
The disclosed method and compositions may be understood more readily by reference to the following detailed description of particular embodiments and the Example included therein and to the Figures and their previous and following description.
It is to be understood that the disclosed method and compositions are not limited to specific synthetic methods, specific analytical techniques, or to particular reagents unless otherwise specified, and, as such, may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
A. Definitions
The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
As used in the specification and the appended claims, the singular forms “a,” “an” and “the” can include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes mixtures of compounds, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.
The word “or” as used herein means any one member of a particular list and also includes any combination of members of that list.
Ranges may be expressed herein as from “about” one particular value, and/or to “about” another particular value. The term “about” is used herein to mean approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 20%. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
As used herein, the term “amino acid sequence” refers to a list of abbreviations, letters, characters or words representing amino acid residues. The amino acid abbreviations used herein are conventional one letter codes for the amino acids and are expressed as follows: A, alanine; C, cysteine; D aspartic acid; E, glutamic acid; F, phenylalanine; G, glycine; H histidine; I isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; and Y, tyrosine.
A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more —OCH2CH2O— units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more —CO(CH2)8CO— moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
“Peptide” as used herein refers to any peptide, oligopeptide, polypeptide, gene product, expression product, or protein. A peptide is comprised of consecutive amino acids. The term “peptide” encompasses naturally occurring or synthetic molecules.
As used herein, the term “Apo E mimetic” is interchangeable with apolipoprotein-E mimicking peptide. Apo E mimetics are peptides that are related to, characteristic of, or mimic Apo E. Apo E mimetics include Apo E peptides (i.e. peptides derived from full length Apo E).
As used herein, “reverse oriented”, “reversed orientation”, “reverse analog” or “reverse sequence” refers to a peptide, or a portion of the peptide, has a reverse amino acid sequence as compared to a non-reverse oriented peptide (i.e., the original sequence is read (or written) from right to left). For example, if one peptide has the amino acid sequence ABCDE, its reverse analog or a peptide having its reverse sequence is as follows: EDCBA. In a dual domain peptide for example, Ac-hE-18A-NH2, either the hE sequence is read from right to left or the 18A sequence is read from right to left. For a reverse analog of, LRKLRKRLLR-DWLKAFYDKVAEKLKEAF (SEQ ID NO:1) can be RLLRKRLKRL-DWLKAFYDKVAEKLKEAF (SEQ ID NO:2) or LRKLRKRLLR-FAEKLKEAVKDYFAKLWD (SEQ ID NO:3).
As used herein a “dual-domain peptide”, a “dual-domain synthetic peptide”, or a “dual-domain Apo E mimicking peptide” is meant to mean a peptide comprising a lipid-associating peptide/domain and a receptor binding peptide/domain.
As used herein a “single-domain peptide”, a “single-domain synthetic peptide”, or a “single-domain Apo E mimicking peptide” is meant to mean a peptide comprising either a lipid-associating peptide/domain or a receptor binding peptide/domain, but not both.
As used herein “domain switched”, “switched domain”, or “switched” peptide is meant to mean that the lipid-associating peptide is covalently linked to the receptor binding domain of apolipoprotein E such that the lipid-associating peptide is at the N-terminus of the synthetic apolipoprotein E-mimicking peptide. For example, the peptide 18A-hE is exemplary of a domain switched peptide.
As used herein, “scrambled” “scrambled version”, or “scrambled peptide” is meant to mean that the composition of the amino acid sequence is the same as the unscrambled peptide, however the sequence of the amino acids is altered thus rendering the peptide unable to form either an α-amphipathic helix or does not possess lipid associating (or HSPG associating) properties. However, in some cases, as described in this invention, the scrambled peptide remains able to form a different helical structure, such as a i-helix. For example, if one peptide has the amino acid sequence ABCDE, the scrambled version of the peptide could have the amino acid sequence DEABC. Scrambled peptides are often denoted as having a “Sc” prior to the portion of the peptide that is scrambled. For example, Sc-hE-18A denoted that the hE portion of the peptide is scrambled.
As used herein, “sample” is meant to mean an animal; a tissue or organ from an animal; a cell (either within a subject, taken directly from a subject, or a cell maintained in culture or from a cultured cell line); a cell lysate (or lysate fraction) or cell extract; or a solution containing one or more molecules derived from a cell or cellular material (e.g. a polypeptide or nucleic acid), which is assayed as described herein. A sample may also be any body fluid or excretion (for example, but not limited to, blood, urine, stool, saliva, tears, bile) that contains cells or cell components.
As used herein, “subject” refers to the target of administration, e.g. an animal. Thus the subject of the disclosed methods can be a vertebrate, such as a mammal. For example, the subject can be a human. The term does not denote a particular age or sex. Subject can be used interchangeably with “individual” or “patient”.
As used herein, “modulate” is meant to mean to alter, by increasing or decreasing.
As used herein “lipid binding domain E” and “lipid-associating peptide” are used interchangeably. As used herein, both terms can mean the lipid binding domain of Apolipoprotein E.
As used herein, “isolated polypeptide” or “purified polypeptide” is meant to mean a polypeptide (or a fragment thereof) that is substantially free from the materials with which the polypeptide is normally associated in nature. The polypeptides of the invention, or fragments thereof, can be obtained, for example, by extraction from a natural source (for example, a mammalian cell), by expression of a recombinant nucleic acid encoding the polypeptide (for example, in a cell or in a cell-free translation system), or by chemically synthesizing the polypeptide. In addition, polypeptide fragments may be obtained by any of these methods, or by cleaving full length proteins and/or polypeptides.
As used herein, “18A” when used in the context of a peptide or peptide sequence refers to the peptide DWLKAFYDKVAEKLKEAF (SEQ ID NO:5). The peptide sequence can occur as an isolated peptide, or as a sequence within a larger peptide sequence.
As used herein, “hE” when used in the context of a peptide or peptide sequence refers to the peptide LRKLRKRLLR (SEQ ID NO:4). The peptide sequence can occur as an isolated peptide, or as a sequence within a larger peptide sequence.
As used herein, “[R]hE” when used in the context of a peptide or peptide sequence refers to the peptide LRRLRRRLLR (SEQ ID NO:11). The peptide sequence can occur as an isolated peptide, or as a sequence within a larger peptide sequence.
As used herein, the term “aliphatic” includes both saturated and unsaturated, straight chain (i.e., unbranched) or branched aliphatic hydrocarbons, which are optionally substituted with one or more functional groups. As will be appreciated by one of ordinary skill in the art, “aliphatic” is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term “alkyl” includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl” and the like. In certain embodiments, as used herein, “lower alkyl” is used to indicate those alkyl groups (substituted, unsubstituted, branched or unbranched) having about 1-6 carbon atoms. “Substituted alkyl” refers to alkyl groups that are substituted with one or more functional groups. Substituents include, but are not limited to, any of the substituents mentioned below, i.e., the substituents recited below resulting in the formation of a stable compound.
As used herein, “alkenyl” denotes a monovalent group derived from a hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
As defined herein, “Cn,” where “n” is an integer, describes a hydrocarbon molecule or fragment (e.g., an alkyl group) wherein “n” denotes the number of carbon atoms in the fragment or molecule.
As used herein, “fatty acid moiety” refers to any molecular species and/or molecular fragment comprising the acyl component of a fatty (carboxylic) acid. That is, a fatty acid moiety is a group encompassing an acyl moiety derivable from a fatty acid, namely being generally of the form RC(═O)—, wherein R represents the aliphatic chain of the corresponding fatty acid.
As used herein the term “fatty acid” is meant to encompass a mono carboxylic acid having an aliphatic chain (“tail”), wherein said aliphatic chain may be either saturated, monounsaturated (having one unsaturated bond anywhere on the aliphatic chain) or poly unsaturated (having at least two unsaturated bonds anywhere on the aliphatic chain). An unsaturated bond on the aliphatic chain may be a double (in the cis and/or trans configuration) or a triple bond. The length of the aliphatic chain (being either saturated, monounsaturated or polyunsaturated) of a fatty acid may vary between 8 and 32 carbon atoms. Fatty acids may be derived from a natural source (either an animal or plant source), synthetic source or semi-synthetic source.
As used herein, the term “fatty acid” includes saturated fatty acids, which do not contain any double or triple bonds in the hydrocarbon chain. Saturated fatty acids include, but are not limited to propionic acid (C3) (by way of example, C3 indicates propionic acid has 3 carbon atoms in its hydrocarbon chain; the number of carbon atoms in the hydrocarbon chain of other example fatty acids is denoted in analogous fashion herein), butyric acid (C4), valeric acid (C5), caproic acid (C6), enanthic acid (C7), caprylic acid (C8), pelargonic acid (C9), capric acid (C10), undecylic acid (C11), lauric acid (C12), tridecylic acid (C13), myristic acid (C14), pentadecylic acid (C15), palmitic acid (C16), margaric acid (C17), stearic acid (C18), isostearic acid (C18), nonadecylic acid (C19), arachidic acid (C20), heneicosylic acid (C21), behenic acid (C22), tricosylic acid (C23), lignoceric acid (C24), pentacosylic acid (C25), cerotic acid (C26), heptacosylic acid (C27), montanic acid (C28), nonacocylic acid (C29), melissic acid (C30), henatriacontylic acid (C31), lacceroic acid (C32), psyllic acid (C33), geddic acid (C34), ceroplastic acid (C35) and hexatriacontylic acid (C36).
As used herein, the term “fatty acid” also includes monounsaturated fatty acids, which contain one double or triple bond in the hydrocarbon chain, and polyunsaturated fatty acids, which contain more than one double and/or triple bond in the hydrocarbon chain. Such acids include, but are not limited to the omega 3, omega 6, omega 9 fatty acids, other fatty acids such as myristoleic and palmitoleic acid and conjugated fatty acids. Examples of monounsaturated and polyunsaturated fatty acids include but are not limited to, (a) omega 3 fatty acids, such as hexadecatrienoic acid (C16:3); (by way of example, C16:3 indicates hexadecatrienoic acid has 16 carbon atoms in its hydrocarbon chain and 3 double bonds; the number of carbon atoms and double bonds in the hydrocarbon chain of other example unsaturated fatty acids is denoted in analogous fashion herein), alpha linolenic acid (C18:3) and eicosapentanoic acid (20:5), (b) omega 6 fatty acids, such as linoleic acid (18:2), docosadienoic acid (C22:2), arachidonic acid (C20:4) and tetracosatetraenoic acid (C24:5), (c) omega 9 fatty acids, such as oleic acid (C18:1), eicosenoic acid (C20:1) and nevronic acid (C24:1), and (d) conjugated fatty acids such as rumenic acid (C18:2), eleostatic acid (C18:3), and rumelenic acid (C18:3).
As used herein, the term “fatty acid” also includes branched fatty acids. Examples of branched fatty acids include, but are not limited to, monomethyl branched fatty acids, such as 14-methyl pentadecanoic acid, 6-methyl caprylic acid, 4-methyl-3-pentenoic acid, (pyroterebic acid), 2-methyl-2E-butenoic acid (tiglic acid), 2-methyl-2Z-butenoic acid (angelic acid), multimethyl branched acids, isoprenoid fatty acids (vittatalactone, all-trans-retinoic acid), branched methoxy fatty acids and hydroxy and other fatty acids such as 2-hydroxyoctanoic acid and 4-oxopentanoic acid (levulinic acid).
The term “fatty acid” also includes mixtures comprising fatty acids such as natural oils or fats which may comprise components that are not fatty acids. Natural oils or fats understood to comprise mixtures of fatty acids include, but are not limited to, animal fats, soya bean oil, coconut oil, palm oil, palm kernel oil, rapeseed oil, cottonseed oil, linseed oil, sunflower oil, fish oil, algae oil, and the like.
The term “ω-amino-fatty acid” refers to fatty acids which feature an amino group at the distal carbon of the hydrocarbon chain thereof. The ω-amino-fatty acid moieties that are used in the context of the present invention can be saturated or unsaturated hydrocarbon chains. These moieties have a carboxylic group at one end of the hydrocarbon chain and an amine group at the other. The hydrocarbon chain connecting the carboxylic and amine groups in such an ω-amino-fatty acid moiety typically has from 3 to 32 carbon atoms.
Exemplary ω-amino-fatty acids include, without limitation, 4-amino-butyric acid, 6-amino-caproic acid, 8-amino-caprylic acid, 10-amino-capric acid (10-amino-decanoic acid), 12-amino-lauric acid (12-amino-dodecanoic acid), 14-amino-myristic acid (14-amino-tetradecanoic acid), 14-amino-myristoleic acid, 16-amino-palmitic acid (16-amino-hexadecanoic acid), 18-amino-stearic acid, 18-amino-oleic acid, 16-amino-palmitoleic acid, 18-amino-linoleic acid, 18-amino-linolenic acid and 20-amino-arachidonic acid.
“Dosing regimen” as used herein refers to at least one treatment cycle followed by at least one rest phase. A dosing regimen can include more than one treatment cycle and more than one rest phase. For example, a dosing regimen can be a three month treatment cycle followed by a one year rest phase. Another example can be a six month treatment cycle followed by a six month rest phase and then a three month treatment cycle followed by a one year rest phase.
“Dose” or “dosage” as used herein refers to a specific quantity of a therapeutic agent, such as an Apo E mimetic, that is taken at specific times.
As used herein, “treat” is meant to mean administer one of the disclosed compositions to a subject, such as a human or other mammal (for example, an animal model), that has atherosclerosis, in order to prevent or delay a worsening of the effects of the disease or condition, or to partially or fully reverse the effects of the disease.
As used herein, “prevent” is meant to mean minimize the chance that a subject who has an increased susceptibility for developing atherosclerosis will develop atherosclerosis.
As used herein, the term “treatment cycle” refers to the administration of Apo E mimetics for an established period of time. A treatment cycle includes a wide range of dosages of Apo E mimetics as well as different lengths of time for administering the Apo E mimetics. For example, a treatment cycle can be a three month period wherein an Apo E mimetic is administered twice a week for the three month period.
As used herein, “effective amount” is meant to mean a sufficient amount of the composition or Apo E mimetic to provide the desired effect. For example, an effective amount of an Apo E mimetic can be an amount that provides a therapeutic affect and provides sustained therapeutic effects after withdrawal of the treatment. An effective amount of an Apo E mimetic is an amount that is able to cause a benefit illustrated by a decrease in atherosclerosis, a decrease in artery wall stiffness, a decrease in isolated systolic hypertension, a decrease in arterial inflammation, an increase in anti-oxidant capability of the HDL fraction and/or an improvement in myocardial function, as well as an amount that allows for a sustained therapeutic effect after withdrawal of the Apo E mimetic. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of disease (or underlying genetic defect) that is being treated, the particular compound used, its mode of administration, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate “effective amount” may be determined by one of ordinary skill in the art using only routine experimentation.
As used herein, “sustained therapeutic effect” is a therapeutic effect that persists after the therapeutic has been withdrawn. For example, the sustained therapeutic effect is maintained even after the acute cholesterol lowering effect is gone.
“Rest phase” as used herein refers to a period of time wherein an Apo E mimetic is not administered.
“Atherosclerotic burden” as used herein is the amount of atherosclerosis in the arteries of a patient. This may include the coronary, carotid, peripheral and other arteries. The atheroma may be complex lesions with a smooth muscle and collagen containing fibrous cap, areas of calcification, cholesterol crystals and cholesterol laden macrophages (foam cells) and/or less complex and more unstable lesions with less calcification and a thinner fibrous cap, and more foam cells and cholesterol (unstable lesions). The unstable lesions may intrude into the lumen of the artery or expand away from the lumen of the artery.
The phrase “lipid disorder” is meant to mean when a subject has an excess of lipids or increased inflammatory lipids in their blood. Lipids include, but are not limited to lipids such as ox-LDL (i.e., oxidized PAPC (1-palmitoyl 2-arachidonyl phophyatidyl choline)). Oxidation of PAPC or PLPC, the lipid components of LDL, produce oxidized lipids. Having a lipid disorder can make one more likely to develop inflammatory disease such as atherosclerosis and heart disease. Lipid disorders can be caused by genetic predispositions or diet.
As used herein, “lipoprotein” or “lipoproteins” is meant to mean a biochemical assembly that contains both proteins and lipids. The lipids or their derivatives may be covalently or non-covalently bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins. Examples include the high density and low density lipoproteins of the blood, the transmembrane proteins of the mitochondrion and the chloroplast, and bacterial lipoproteins
As used herein, “high-density lipoprotein” (HDL) is meant to mean a class of lipoproteins, varying somewhat in their size (8-11 nm in diameter), that can transport cholesterol. HDL cholesterol is cholesterol that is associated with HDLs. About one-fourth to one-third of blood cholesterol is carried by high-density lipoprotein (HDL). HDL cholesterol is known as “good” cholesterol, because high levels of HDL seem to protect against heart attack. Low levels of HDL (less than 40 mg/dL in men and less than 50 mg/dL in women) also increase the risk of heart disease. Medical experts think that HDL tends to carry cholesterol away from the arteries and back to the liver, where it is passed from the body. Some experts believe that that HDL removes excess cholesterol from arterial plaque, thus slowing its buildup
As used herein, “very Low Density Lipoproteins” (VLDL) is meant to mean a lipoprotein subclass. It is assembled in the liver from cholesterol and apolipoproteins. It is converted in the bloodstream to low density lipoprotein (LDL). VLDL particles have a diameter of 30-80 nm. VLDL transports endogenous products where chylomicrons transport exogenous (dietary) products.
As used herein, “low-density lipoprotein” or “LDL” is meant to mean a lipoprotein that varies in size (approx. 22 nm) and can contain a changing number of triglycerides and cholesteryl esters they actually have a mass and size distribution. Each native LDL particle contains a single apolipoproteinB-100 molecule (Apo B-100, a protein with 4536 amino acid amino acid residues) and a phospholipid coat that circles the triglycerides and cholesteryl esters, keeping them soluble in the aqueous environment. LDL is commonly referred to as bad cholesterol. LDL cholesterol is cholesterol that is associated with LDLs. When too much LDL cholesterol circulates in the blood, it can slowly build up in the inner walls of the arteries that feed the heart and brain. Together with other substances, it can form plaque, a thick, hard deposit that can narrow the arteries and make them less flexible. This condition is known as atherosclerosis. If a clot forms and blocks a narrowed artery, then heart attack or stroke can result.
Cholesterol cannot dissolve in the blood. It has to be transported to and from the cells by carriers called lipoproteins. LDLs and HDLs along with triglyceride-rich lipoproteins (VLDL) and Lp(a) cholesterol, make up your total cholesterol count, which can be determined through a blood test.
The phrase “nucleic acid” as used herein refers to a naturally occurring or synthetic oligonucleotide or polynucleotide, whether DNA or RNA or DNA-RNA hybrid, single-stranded or double-stranded, sense or antisense, which is capable of hybridization to a complementary nucleic acid by Watson-Crick base-pairing. Nucleic acids of the invention can also include nucleotide analogs (e.g., BrdU), and non-phosphodiester internucleoside linkages (e.g., peptide nucleic acid (PNA) or thiodiester linkages). In particular, nucleic acids can include, without limitation, DNA, RNA, cDNA, gDNA, ssDNA, dsDNA or any combination thereof
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed method and compositions belong. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present method and compositions, the particularly useful methods, devices, and materials are as described. Publications cited herein and the material for which they are cited are hereby specifically incorporated by reference. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention. No admission is made that any reference constitutes prior art. The discussion of references states what their authors assert, and applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of publications are referred to herein, such reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art.
B. Apo E-mimicking Peptides
Disclosed are apolipoprotein E-mimicking peptides or Apo E mimetics. Non-limiting examples of the Apo E-mimicking peptides are provided herein. The Apo E-mimicking peptides can be single domain or dual domain peptides. Compositions containing the Apo E-mimicking peptides are also disclosed.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an acetylated amino hexanoic acid (Ac-Aha).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the Ac-Aha is at the N-terminus of the peptide. In some aspects the Aha can be inserted between the lipid-associating peptide comprises a class A amphipathic-helical domain.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain. For example, the class A amphipathic-helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein said apolipoprotein E can be from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein said synthetic peptide is protected using an amide group at the C-terminus.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), or RLTRKRGLK (SEQ ID NO:13). The receptor binding domain of ApoE can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO:4), LRKLPKRLLR (SEQ ID NO:8), LRNVRKRLVR (SEQ ID NO:9), MRKLRKRVLR (SEQ ID NO:10), LRRLRRRLLR (SEQ ID NO:11), LRKLRKRFFR (SEQ ID NO:12), LRKLRKRLLR (SEQ ID NO:4), or LRKMRKRLMR (SEQ ID NO:7).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), RLTRKRGLK (SEQ ID NO:13), LRRMRRRLMR (SEQ ID NO:621), or RLTRRRGK (SEQ ID NO:622).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2. The ApoE-mimicking peptide of Ac-Aha-hE18A-NH2 is Ac-Aha-LRKLRKRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO:1). The ApoE-mimicking peptide of Ac-Aha-[R]hE18A-NH2 is Ac-Aha-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2. (SEQ ID NO:662)
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an acetylated ω-amino fatty acid moiety, wherein the acetylated ω-amino fatty acid moiety is at the N-terminus of the peptide. In some aspects the ω-amino fatty acid moiety can be inserted between the lipid-associating peptide comprises a class A amphipathic-helical domain.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain. For example, the class A amphipathic-helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain, wherein the receptor binding domain of ApoE can be covalently linked to the lipid-associating peptide.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein said apolipoprotein E can be from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein said synthetic peptide is protected using an amide group at the C-terminus.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), or RLTRKRGLK (SEQ ID NO:13). The receptor binding domain of ApoE can also be, but is not limited to, LRKLRKRFFR (SEQ ID NO:4), LRKLPKRLLR (SEQ ID NO:8), LRNVRKRLVR (SEQ ID NO:9), MRKLRKRVLR (SEQ ID NO:10), LRRLRRRLLR (SEQ ID NO:11), LRKLRKRFFR (SEQ ID NO:12), LRKLRKRLLR (SEQ ID NO:4), or LRKMRKRLMR(SEQ ID NO:7).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the receptor binding domain of ApoE can be LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), RLTRKRGLK (SEQ ID NO:13), LRRMRRRLMR (SEQ ID NO:621), or RLTRRRGK (SEQ ID NO:622).
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the synthetic ApoE-mimicking peptide can be: butanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 623); hexanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 624); octanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625); decanoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 626); lauroyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 627); myristoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628); palmitoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 629); stearoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 630); palmitoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 631); arachidoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 632); behenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 633); oleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 634); ricinoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 635); linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 636); vacceoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 637); gadoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 638); erucoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 6239); cetoleoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 640); nervonoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 641); adrenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 642); α-linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 643); γ-linolenoyl-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 644); EPA-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 645); or DHA-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 646).
In the foregoing, the fatty acid moiety is shown at the left side and is linked to the peptide LRRLRRRLLR (SEQ ID NO:11). “EPA” indicates a moiety derived from 5,8,11,14,17-eicosapentaenoic acid; and “DHA” indicates a moiety derived from 4,7,10,13,16,19-docosahexaenoic acid.
Disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety derived from a natural oil or fat, e.g. fish oil, wherein the synthetic ApoE-mimicking peptide can be: (fish oil)-LRRLRRRLLR-DWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO:663). In the foregoing “(fish oil)” indicates that the fatty acids in fish oil, including, but not limited to, fish oil components such as EPA and DHA, are linked to linked to the peptide LRRLRRRLLR (SEQ ID NO:11). Thus, the synthetic ApoE-mimicking peptide is a mixture of peptides comprising fatty acid groups derived from the fish oil used to prepare them.
In some instances, the synthetic ApoE-mimicking peptide can be any of the disclosed peptides comprising a fatty acid.
In some instances, the synthetic ApoE-mimicking peptide can be any of the disclosed peptides comprising an acetylated fatty acid.
Also disclosed are synthetic ApoE-mimicking peptides comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha, wherein the receptor binding domain of apolipoprotein E is scrambled. Examples of scrambled receptor binding domains of ApoE are provided below.
Also disclosed are synthetic apolipoprotein E-mimicking peptide, consisting of: a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein receptor binding domain is covalently linked to said lipid-associating peptide, wherein both the receptor binding domain of apolipoprotein E and the lipid-associating peptide are scrambled. Examples of scrambled receptor binding domains of ApoE and scrambled lipid-associating peptides are provided below.
Apolipoprotein E-mimicking peptides have both direct cholesterol lowering effects by providing an alternative ligand for receptors on the liver to clear atherogenic Apolipoprotein B containing lipoproteins (LDL, VLDL, and β-VLDL), and direct beneficial effects on the artery wall. New, more effective methods of imaging coronary atherosclerosis allow for direct measurement of benefits to the artery wall (Van Velzen, et al. Hellenic J Cardiol 50: 245-263, 2009). The Apo E-mimicking peptides can enhance the removal of cholesterol from the artery wall, working in conjunction with HDL, increasing the formation of lipid poor preβ-HDL that accept cholesterol from macrophages. The Apo E-mimicking peptides can stimulate macrophage-mediated clearance of dead and dying cells in the artery wall (efferocytosis), improve the quality of HDL by increasing PON-1 levels and bringing down plasma lipid hydroperoxide levels, decrease macrophage content in atherosclerotic lesions resulting in more stable lesions, and decrease inflammation in the artery wall. As a result, the Apo E-mimicking peptides reduce the size of atherosclerotic lesions more rapidly than apoA-I mimetic peptides and more rapidly than the statins (HMG-CoA reductase inhibitors). Atherosclerotic lesion regression persists in Apo E-mimicking peptides treated animals even when cholesterol levels are the same as in saline treated animals. Thus, the effects cannot be simply explained by cholesterol lowering.
1. Apolipoprotein E
Apolipoprotein E (Apo E) plays an important role in the metabolism of triglyceride-rich lipoproteins, such as very low density lipoprotein (VLDL) and chylomicrons. Apolipoprotein E mediates the high affinity binding of Apo E-containing lipoproteins to the low density lipoprotein (LDL) receptor (Apo B, E receptor) and the members of its gene family, including LDL receptor related protein (LRP), very low density lipoprotein receptor (VLDLR) and the Apo E2 receptor (Apo E2R) (Mahley, R. W., (1988) Science 240, 622-630). The putative and complex role of Apo E in atherosclerosis has been emphasized by several observations: (i) mice that over express human Apo E have lower levels of total plasma cholesterol levels (Shimono, H. N., et al., (1992) Eur. J. Clin. Invest. 90, 2084-2991), (ii) intravenous injection of human Apo E into cholesterol-fed rabbits protects these animals from atherosclerosis (Yamada, et al., (1989) Proc. Natl. Acad. Sci. U.S.A. 86, 665-669), and (iii) loss of the Apo E gene in mice produces spontaneous atherosclerosis (Zhang, S. H., et al., (1992) Science 258, 468-471) which is ameliorated when macrophage-specific apo E expression is initiated in Apo E-deficient mice (Spangenberg, J., et al., (1997) Biochem. Biophys. Acta 1349, 109-121).
Apo E is a protein that binds lipid and has two major domains (Mahley, R. W., et al. J. Lipid Res. 1999, 40:622-630). The 22 kDa amino terminal domain has been shown by X-ray crystallographic studies to be a 4-helix bundle (Wilson, C., et al. Science 1991; 252:1817-1822) and to contain a positively-charged receptor binding domain. For this region to mediate very low-density lipoprotein (VLDL) binding to its receptors, the apolipoprotein must associate with the lipoprotein surface; this is enabled by the C-terminal amphipathic helical region. If the 4-helix bundle that contains the positively charged receptor-binding domain does not open up on the lipoprotein surface, then the VLDL is defective in binding to receptors. Thus, the positively charged arginine (Arg)-rich cluster domain of the Apo E and the C-terminal amphipathic helical domain, are both required for the enhanced uptake of atherogenic Apo E-containing lipoproteins.
Apo E is secreted as a 299 amino acid residue protein with a molecular weight of 34,200. Based on thrombin cleavage of Apo E into two fragments, a two-domain hypothesis was initially suggested to explain the fact that the C-terminal region of Apo E (192-299) is essential for its binding to hypertriglyceridemic VLDL and the N-terminal 22 kDa domain (1-191), binds to the LDL-R (Bradley, W. A., et al., (1986) J. Lipid Res. 27, 40-48). Additional physical-chemical characterization of the protein and its mutants have extended this concept and have shown that the region 192-211 binds to phospholipid while the amino terminal domain (1-191) is a globular structure that contains the LDL receptor binding domain in the 4-helix bundle (Wilson, C., et al., (1991) Science 252, 1817-1822). Studies with synthetic peptides (Sparrow et al. Biochemistry 31(4):1065-8, 1992) and monoclonal antibodies pinpointed the LDL receptor binding domain of apo E between residues 129-169, a domain enriched in positively charged amino acids, Arg and Lys (Rall, S. C., Jr., et al., (1982) PNAS USA 79, 4696-4700; Lalazar, A., et al., (1988) J. Biol. Chem. 263, 3542-2545; Dyer, C. A., et al., (1991) J. Biol. Chem. 296, 22803-22806; and Dyer, C. A., et al., (1991) J. Biol. Chem. 266, 15009-15015).
To test the hypothesis that a minimal arginine-rich Apo E receptor binding domain (141-150) was sufficient to enhance low density lipoprotein (LDL) and very low density lipoprotein (VLDL) uptake and clearance when covalently linked to a class A amphipathic helix, a peptide was synthesized in which the receptor binding domain of human Apo E, LRKLRKRLLR (SEQ ID NO:4) (hApo E[141-150] also referred to as “hE”), was linked to 18A, a well characterized high affinity lipid-associating peptide (DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), also referred to as “18A”) to produce a peptide denoted as hApo E[141-150]-18A (also referred to as “hE-18A”) (see U.S. Pat. No. 6,506,880, which is hereby incorporated by reference in its entirety for its teaching of specific Apo E mimetics and their uses). Also synthesized was an end protected analog of hE-18A, denoted Ac-hE18A-NH2. The importance of the lysine residues and the role of the hydrophobic residues in the receptor binding domain were also studied using two analogs, LRRLRRRLLR (SEQ ID NO:11)-18A (also referred to as “hE(R)-18A”) and LRKMRKRLMR (SEQ ID NO:7)-18A (also referred to as “mE18A”), whereby the receptor binding domain of human Apo E was modified to substitute arginine (R) residues for lysine (K) residues at positions 143 and 146 (LRRLRRRLLR; SEQ ID NO:11) and whereby the receptor binding domain of mouse Apo E (LRKMRKRLMR; SEQ ID NO:7), were linked to 18A, respectively. The effect of the dual character peptides on the uptake and degradation of human LDL/VLDL by cells was then determined.
It was determined that in MEF 1 cells with induced LDL receptors, LDL internalization was enhanced three, five and seven times by Ac-mE-18A-NH2, Ac-hE-18A-NH2, and Ac-hE(R)-18A-NH2 respectively. All three peptides increased degradation of LDL by 100 percent. Both Ac-hE-18A-NH2 and the control peptide Ac-18A-NH2 interacted with VLDL to cause a displacement of apo E from VLDL. However, only Ac-hE-18A-NH2-associated VLDL enhanced the uptake of VLDL six fold and degradation three fold compared to VLDL alone in spite of the absence of apoE. The LDL binding to fibroblasts in the presence of these peptides was not saturable, however, over the LDL concentration range studied.
Furthermore, a similar enhancement of LDL internalization independent of the presence of the LDL receptor related protein (LRP) or LDL receptor or both was seen. Pretreatment of cells with heparinase and heparitinase however abolished greater than 80% of enhanced peptide-mediated LDL uptake and degradation by cells. The data indicated that the dual-domain peptides enhanced LDL uptake and degradation by binding to the LDL through the amphipathic lipid binding domain (18A). However, the minimal 141-150 Arg-rich domain did not decrease LDL levels but did so only in combination with 18A lipid associating domain, did not confer LDL-receptor binding but directed the LDL-peptide complex to the HSPG pathway for uptake and degradation by fibroblasts.
2. Fatty Acids
The disclosed peptides can be linked to a fatty acid moiety, an ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety. In various aspects, the fatty acid moiety, the ω-amino fatty acid moiety, or the acetylated ω-amino fatty acid moiety is linked to a disclosed peptide via the N-terminal amino group of the peptide.
In various aspects, the linkage between the fatty acid moiety, the ω-amino fatty acid moiety, or the acetylated ω-amino fatty acid moiety and the N-terminal amino group of the peptide has the a structure represented by the following formulas, respectively:
Figure USRE050320-20250304-C00001
wherein A is an aliphatic group have 2-32 carbon atoms. In a further aspect, the aliphatic group is an alkyl group. In a still further aspect, the aliphatic group comprises 0-3 double bonds. In a yet further aspect, the aliphatic group is an alkenyl group.
In a further aspect, the fatty acid moiety linked to the disclosed peptide is derived from a purified fatty acid. In a still further aspect, the fatty acid moiety linked to the disclosed peptide is derived from a saturated fatty acid. In a yet further aspect, the fatty acid moiety linked to the disclosed peptide is derived from an unsaturated fatty acid. In an even further aspect, the unsaturated fatty acid is a polyunsaturated fatty acid with two or more double bonds.
In various aspects, the synthetic ApoE-mimicking peptide comprises a fatty acid moiety.
Exemplary fatty acids from which a fatty acid moiety is derived include, without limitation, butyric acid, caproic acid, caprylic acid, capric acid, decanoic acid, lauric acid, myristic acid, palmitic acid, pentadecanoic acid, stearic acid, arachidic acid, behenic acid, erucic acid, lignoceric acid, margaric acid, myristoleic acid, palmitoleic acid, oleic acid, gadoleic acid, ricinoleic acid, vaccenic acid, linoleic acid, linolenic acid, alpha-linolenic acid, gamma-linolenic acid, licanic acid, margaroleic acid, arachidic acid, gadoleic acid, nervonic acid, arachidonic acid, docosapentaenoic (DPA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and the like.
Exemplary saturated fatty acids include, but are not limited to, propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid, pentadecanoic acid, hexadecanoic acid, heptadecanoic acid, octadecanoic acid, nonadecanoic acid, eicosanoic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, tetracosanoic acid, pentacosanoic acid, hexacosanoic acid, heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoic acid, henatriacontanoic acid, dotriacontanoic acid, tritriacontanoic acid, tetratriacontanoic acid, pentatriacontanoic acid, and hexatriacontanoic acid.
Exemplary unsaturated fatty acids include, but are not limited to, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA), erucic acid, docosahexaenoic acid (DHA), and docosapentaenoic acid.
In various aspects, the fatty acid moiety linked to the disclosed peptide is derived from an unpurified fatty acid or mixture of fatty acids such as natural oil or fat. Typically, a natural oil or fat is a heterogeneous mixture of generally hydrophobic compounds comprising one or more fatty acids. The fatty acid source may comprise a natural oil or fat, such as (but not limited to) animal fats, biological oils, or vegetable oils such as soya bean oil, coconut oil, palm oil, palm kernel oil, rapeseed oil, cottonseed oil, linseed oil, sunflower oil, fish oil, algae oil, and the like.
In a further aspect, the natural oil or fat is one that contains or is enriched for one or more omega-3 fatty acids, for example, marine oil, for example, fish oil, krill oil and algae oil. Any oil containing DHA and/or EPA can be used. In a further aspect, the natural oil or fat contains at least 70% or about 70%, by weight, DHA, for example, at least 75% or about 75%, at least 80% or about 80%, at least 85% or about 85%, or at least 90% or about 90%, by weight, DHA. In a still further aspect, the natural oil or fat contains between 5% or about 5% and 15% or about 15% EPA, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15%, by weight, EPA. In a yet further aspect, the natural oil or fat contains not more than 10% or about 10% EPA or less than 10% or about 10%, EPA.
In a further aspect, the fatty acid moiety is derived from an omega-3 fatty acid. As used herein, the term “omega-3 polyunsaturated fatty acid(s)” or “omega-3 fatty acid” refers to a family of unsaturated fatty carboxylic acids that have in common a carbon-carbon bond in the n-3 position (i.e., the third bond from the methyl end of the molecule). Typically, they contain from about 16 to about 24 carbon atoms and from three to six carbon-carbon double bonds. Omega-3 polyunsaturated fatty acids can be found in nature, and these natural omega-3 polyunsaturated fatty acids frequently have all of their carbon-carbon double bonds in the cis-configuration.
Exemplary omega-3 fatty acids include, but are not limited to, 7,10,13-hexadecatrienoic acid (sometimes abbreviated as 16:3 (n-3)); 9,12,15-octadecatetrienoic acid (α-linolenic acid (ALA), 18:3 (n-3)); 6,9,12,15-octadecatetraenoic acid (stearidonic acid (STD), 18:4 (n-3)); 11,14,17-eicosatrienoic acid (eicosatrienoic acid (ETE), 20:3 (n-3)); 8,11,14,17-eicosatetraenoic acid (eicosatetraenoic acid (ETA), 20:4 (n-3)); 5,8,11,14,17-eicosapentaenoic acid (eicosapentaenoic acid (EPA), (20:5 (n-3)); 7,10,13,16,19-docosapentaenoic acid (docosapentaenoic acid (DPA), 22:5 (n-3)); 4,7,10,13,16,19-docosahexaenoic acid (docosahexaenoic acid (DHA), 22:6 (n-3)); 9,12,15,18,21-tetracosapentaenoic acid (tetracosapentaenoic acid, 24:5 (n-3)); and 6,9,12,15,18,21-tetracosahexaenoic acid (tetracosahexaenoic acid, 24:6 (n-3)). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in nature in fish oils, and have been used in a variety of dietary/therapeutic compositions.
Various lengths of fatty acids are contemplated. In one aspect, a fatty acid comprises a chain length between C6 and C24, C10 and C24, C10 and C28, or C10 and C32, including synthetic fatty acids with odd carbon numbers. In a further aspect, a fatty acid comprises a chain length selected from the group consisting of: C10, C12, C14, C16, C18, C20, C20, C22 and C24. In a still further aspect, the fatty acid has a chain length selected from the group consisting of C14, C16 and C18. In a yet further aspect, the fatty acid has a chain length selected from the group consisting of C13, C15 and C17. In a still further aspect, the fatty acid has between 4 and 28 carbons.
In various aspects of the present invention, the fatty acid aliphatic chain comprises 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, or 32 carbon atoms.
In various aspects, the fatty acid is a naturally-occurring fatty acid. In a further aspect, the fatty acid is a short chain fatty acid (e.g., less than six carbons), a medium chain fatty acid (e.g., 6-12 carbons), long chain fatty acids (e.g., longer than 12 carbons), or a very long chain fatty acid (e.g., longer than 22 carbons). In a still further aspect, the fatty acid is an unsaturated fatty acid in the cis configuration. In still another embodiment, the fatty acid is an unsaturated fatty acid in the trans configuration.
In various aspects, the synthetic ApoE-mimicking peptide comprises a ω-amino fatty acid moiety.
Exemplary ω-amino-fatty acid moieties are derived from ω-amino-fatty acids including, without limitation, 4-amino-butyric acid, 6-amino-caproic acid, 8-amino-caprylic acid, 10-amino-capric acid (10-amino-decanoic acid), 12-amino-lauric acid (12-amino-dodecanoic acid), 14-amino-myristic acid (14-amino-tetradecanoic acid), 14-amino-myristoleic acid, 16-amino-palmitic acid (16-amino-hexadecanoic acid), 18-amino-stearic acid, 18-amino-oleic acid, 16-amino-palmitoleic acid, 18-amino-linoleic acid, 18-amino-linolenic acid and 20-amino-arachidonic acid. In a further aspect, the ω-amino-fatty acid moieties are derived from 6-amino-caproic acid.
In further aspects, the ω-amino fatty acid moiety is 4-amino-butanoyl, 6-amino-caproyl, 8-amino-octanoyl, 10-amino-decanoyl, 12-amino-lauroyl, 14-amino-myristoyl, 14-amino-myristoleoyl, 16-amino-palmiteoyl, 18-amino-stearoyl, 18-amino-oleoyl, 16-amino-palmitoleoyl, 18-amino-linoleoyl, 18-amino-linolenoyl, or 20-amino-arachidonoyl. In a still further aspect, ω-amino fatty acid moiety is 6-amino-caproyl (or alternatively referred to as 6-amino hexanoyl).
In various aspects, the ω-amino-fatty acid moiety is derived from a ω-amino-fatty acid having the structure:
Figure USRE050320-20250304-C00002
wherein A is an aliphatic group have 2-32 carbon atoms. In a further aspect, the aliphatic group is an alkyl group. In a still further aspect, the aliphatic group comprises 0-3 double bonds. In a yet further aspect, the aliphatic group is an alkenyl group. In various aspects, A is —(CH2)5—.
In a further aspect, the ω-amino-fatty acid moiety is linked to the peptide via the N-terminal amino group of the peptide, and following linking to the peptide, the ω-amino-fatty acid moiety has the structure:
Figure USRE050320-20250304-C00003
wherein A is an aliphatic group have 2-32 carbon atoms. In a further aspect, the aliphatic group is an alkyl group. In a still further aspect, the aliphatic group comprises 0-3 double bonds. In a yet further aspect, the aliphatic group is an alkenyl group. In various aspects, A is —(CH2)5—.
In various aspects, the synthetic ApoE-mimicking peptide comprises an acetylated ω-amino fatty acid moiety. In a further aspect, the disclosed peptides can be linked any of the disclosed ω-amino-fatty acids, and then further comprise an acetyl moiety on the ω-amino group.
In a further aspect, the ω-amino-fatty acid moiety is linked to the peptide via the N-terminal amino group of the peptide, and following linking to the peptide, the ω-amino group is acetylated, and the ω-amino-fatty acid moiety has the structure:
Figure USRE050320-20250304-C00004
wherein A is an aliphatic group have 2-32 carbon atoms. In a further aspect, the aliphatic group is an alkyl group. In a still further aspect, the aliphatic group comprises 0-3 double bonds. In a yet further aspect, the aliphatic group is an alkenyl group. In various aspects, A is —(CH2)5—.
The fatty acids from which the fatty acid moiety is derived are commercially available and can be prepared by different chemical methods (Recent Developments in the Synthesis of Fatty Acid Derivatives, Editors: Knothe G and Derksen J T B, AOCS Press 1999, ISBN 1-893997-00-6.)
3. Single Domain Peptides
Disclosed are single-domain synthetic Apo E mimetics. The single-domain synthetic Apo E mimetics can consist of a receptor binding domain of Apo E or a lipid-associating peptide.
i. Receptor Binding Domain Peptides
The receptor binding domain peptide for the synthetic Apo E mimetics can be a human receptor binding domain peptide of Apo E. For example, receptor binding domain peptide of the disclosed synthetic Apo E mimetics can comprise the amino acid sequence of LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), or LRKLRKRFFR (SEQ ID NO:12). The receptor binding domain peptide of such synthetic Apo E mimetics can also be from a species selected from the group consisting of mouse, rabbit, monkey, rat, bovine, pig and dog.
Examples of receptor binding domain peptides that can be used in the disclosed synthetic Apo E mimetics are provided in Table 1.
TABLE 1
Disclosed Synthetic Apo E mimetics
Starting
Residue
Species  NO: Sequence
Human 141 LRKLRKRLLR (SEQ ID NO: 4)
Rabbit 134 LRKLRKRLLR (SEQ ID NO: 4)
Monkey 141 LRKLRKRLLR (SEQ ID NO: 4)
Mouse 133 LRKMRKRLMR (SEQ ID NO: 7)
Rat 133 LRKMRKRLMR (SEQ ID NO: 7)
Bovine 140 LRKLPKRLLR (SEQ ID NO: 8)
Pig 140 LRNVRKRLVR (SEQ ID NO: 9)
Dog 133 MRKLRKRVLR (SEQ ID NO: 10)
R Modified 141 LRRLRRRLLR (SEQ ID NO: 11)
F Modified 141 LRKLRKRFFR (SEQ ID NO: 12)
ApoB RLTRKRGLK (SEQ ID NO: 13)
The italicized residues in Table 1 indicate changes from the human sequence; however, the property of the amino acid is conserved. The bold-italicized residues in Table 1 indicate the difference from the human sequence at that position.
The receptor binding domain peptide for the synthetic Apo E mimetics can also be the LDL receptor (LDLR) binding domain of apolipoprotein B (ApoB). The LDL receptor (LDLR) binding domain of ApoB can have the sequence RLTRKRGLK (SEQ ID NO:13). ApoB-100 is a 550,000 Da glycoprotein with nine amino acids (3359-3367) serving as the binding domain for the LDL receptor (Segrest et al., J. Lipid. Res. 42, pp. 1346-1367 (2001)). Upon binding to LDLR in clathrin coated pits, LDL is internalized via endocytosis and moves into the endosome where a drop in pH causes the receptor to dissociate from the LDL. The receptor is recycled back to the surface of the cell while the LDL is moved into the lysosome where the particle is degraded (Goldstein et al., Ann. Rev. Cell Biol. 1, pp. 1-39 (1985)). The LDL receptor (LDLR) binding domain of ApoB when used with the disclosed peptides can also be altered and/or modified as described throughout this application for Apo E. For example, LDL receptor (LDLR) binding domain of ApoB can be used with the disclosed lipid-associating peptides, wherein the LDL receptor (LDLR) binding domain of ApoB is covalently linked to said lipid-associating peptide. In addition, the LDL receptor (LDLR) binding domain of ApoB can be scrambled, reverse-oriented, can be part of a domain switched peptide as described below.
ii. Lipid-Associating Peptides
Lipid-associating peptides can be used alone or in combination with the Apo E-mimicking peptides. The lipid associating peptide for these synthetic Apo E mimetics can be, but are not limited to, class A amphipathic helical peptides, class A amphipathic helical peptide mimetics of apoA-I having aromatic or aliphatic residues in the non-polar face, small peptides including pentapeptides, tetrapeptides, tripeptides, dipeptides and pairs of amino acids, Apo-J (G* peptides), and peptide mimetics, e.g., as described below.
a. Class A Amphipathic Helical Peptides
In one aspect, the lipid-associating peptides for use in the disclosed methods include class A amphipathic helical peptides, e.g. as described in U.S. Pat. No. 6,664,230, and PCT Publications WO 02/15923 and WO 2004/034977. It was discovered that peptides comprising a class A amphipathic helix (“class A peptides”), are capable of mitigating one or more symptoms of atherosclerosis as well as treating other disorders.
Class A peptides are characterized by formation of an α-helix that produces a segregation of polar and non-polar residues thereby forming a polar and a nonpolar face with the positively charged residues residing at the polar-nonpolar interface and the negatively charged residues residing at the center of the polar face (see, e.g., Anantharamaiah (1986) Meth. Enzymol, 128: 626-668). It is noted that the fourth exon of apo A-I, when folded into 3.667 residues/turn produces a class A amphipathic helical structure.
One class A peptide, designated 18A (see, e.g., Anantharamaiah (1986) Meth. Enzymol, 128: 626-668) was modified as described herein to produce peptides orally administrable and highly effective at inhibiting or preventing one or more symptoms of atherosclerosis and/or other indications described herein. Without being bound by a particular theory, it is believed that the disclosed peptides can act in vivo by picking up seeding molecule(s) that mitigate oxidation of LDL.
Increasing the number of Phe residues on the hydrophobic face of 18A can increase lipid affinity as determined by the computation described by Palgunachari et al. (1996) Arteriosclerosis, Thrombosis, & Vascular Biol. 16: 328-338. Theoretically, a systematic substitution of residues in the nonpolar face of 18A with Phe could yield six peptides. Peptides with an additional 2, 3 and 4 Phe would have theoretical lipid affinity (2) values of 13, 14 and 15 units, respectively. However, the λ values jumped four units if the additional Phe were increased from 4 to 5 (to 19λ units). Increasing to 6 or 7 Phe would produce a less dramatic increase (to 20 and 21λ units, respectively).
A number of these class A peptides were made including, the peptide designated 4F, D4F, 5F, and D5F, and the like. Various class A peptides inhibited lesion development in atherosclerosis-susceptible mice and rabbits. In addition, the peptides show varying, but significant degrees of efficacy in mitigating one or more symptoms of the various pathologies described herein. A number of such peptides are illustrated in Table 2.
TABLE 2
Class A peptides.
Peptide
Name Amino Acid Sequence
18F D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ ID NO: 5)
 2F Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 5)
 3F Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 14)
 3F14 Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 15)
 4F Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 16)
 5F Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 17)
 6F Ac-D-W-L-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 18)
 7F Ac-D-W-F-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 19)
Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 20)
Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 21)
Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 22)
Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 23)
Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 24)
Ac-E-W-L-K-L-F-Y-E-K-V-L-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 25)
Ac-E-W-L-K-A-F-Y-ID-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 26)
Ac-E-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 27)
Ac-E-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 28)
Ac-E-W-L-K-A-F-Y-D-K-V-F-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 29)
Ac-E-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 30)
Ac-E-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 31)
Ac-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 32)
Ac-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 33)
Ac-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 34)
Ac-A-F-Y-D-K-F-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 35)
Ac-A-F-Y-D-K-F-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 36)
Ac-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 37)
Ac-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 38)
Ac-A-F-Y-D-K-V-F-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 39)
Ac-A-F-Y-D-K-V-F-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 40)
Ac-A-F-Y-D-K-V-A-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 41)
Ac-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-NH2 (SEQ ID NO: 42)
Ac-L-F-Y-E-K-V-L-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 43)
Ac-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 44)
Ac-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 45)
Ac-A-F-Y-D-K-V-F-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 46)
Ac-A-F-Y-D-K-V-F-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 47)
Ac-A-F-Y-D-K-V-A-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 48)
Ac-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 49)
Ac-D-W-L-K-A-L-Y-D-K-V-A-E-K-L-K-E-A-L-NH2 (SEQ ID NO: 50)
Ac-D-W-F-K-A-F-Y-E-K-V-A-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 51)
Ac-D-W-F-K-A-F-Y-E-K-F-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 52)
Ac-E-W-L-K-A-L-Y-E-K-V-A-E-K-L-K-E-A-L-NH2 (SEQ ID NO: 53)
Ac-E-W-L-K-A-F-Y-E-K-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 54)
Ac-E-W-F-K-A-F-Y-E-K-V-A-E-K-L-K-E-F-F-NH2 (SEQ ID NO: 55)
Ac-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 56)
Ac-E-W-L-K-A-F-Y-E-K-F-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 57)
Ac-E-W-F-K-A-F-Y-E-K-F-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 58)
Ac-D-F-L-K-A-W-Y-D-K-V-A-E-K-L-K-E-A-W-NH2 (SEQ ID NO: 59)
Ac-E-F-L-K-A-W-Y-E-K-V-A-E-K-L-K-E-A-W-NH2 (SEQ ID NO: 60)
Ac-D-F-W-K-A-W-Y-D-K-V-A-E-K-L-K-E-W-W-NH2 (SEQ ID NO: 61)
Ac-E-F-W-K-A-W-Y-E-K-V-A-E-K-L-K-E-W-W-NH2 (SEQ ID NO: 62)
Ac-D-K-L-K-A-F-Y-D-K-V-F-E-W-A-K-E-A-F-NH2 (SEQ ID NO: 63)
Ac-D-K-W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L-NH2 (SEQ ID NO: 64)
Ac-E-K-L-K-A-F-Y-E-K-V-F-E-W-A-K-E-A-F-NH2 (SEQ ID NO: 65)
Ac-E-K-W-K-A-V-Y-E-K-F-A-E-A-F-K-E-F-L-NH2 (SEQ ID NO: 66)
Ac-D-W-L-K-A-F-V-D-K-F-A-E-K-F-K-E-A-Y-NH2 (SEQ ID NO: 67)
Ac-E-K-W-K-A-V-Y-E-K-F-A-E-A-F-K-E-F-L-NH2 (SEQ ID NO: 68)
Ac-D-W-L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F-NH2 (SEQ ID NO: 69)
Ac-E-W-L-K-A-F-V-Y-E-K-V-F-K-L-K-E-F-F-NH2 (SEQ ID NO: 70)
Ac-D-W-L-R-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 71)
Ac-E-W-L-R-A-F-Y-E-K-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 72)
Ac-D-W-L-K-A-F-Y-D-R-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 73)
Ac-E-W-L-K-A-F-Y-E-R-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 74)
Ac-D-W-L-K-A-F-Y-D-K-V-A-E-R-L-K-E-A-F-NH2 (SEQ ID NO: 75)
Ac-E-W-L-K-A-F-Y-E-K-V-A-E-R-L-K-E-A-F-NH2 (SEQ ID NO: 76)
Ac-D-W-L-K-A-F-Y-D-K-V-A-E-K-L-R-E-A-F-NH2 (SEQ ID NO: 77)
Ac-E-W-L-K-A-F-Y-E-K-V-A-E-K-L-R-E-A-F-NH2 (SEQ ID NO: 78)
Ac-D-W-L-K-A-F-Y-D-R-V-A-E-R-L-K-E-A-F-NH2 (SEQ ID NO: 79)
Ac-E-W-L-K-A-F-Y-E-R-V-A-E-R-L-K-E-A-F-NH2 (SEQ ID NO: 80)
Ac-D-W-L-R-A-F-Y-D-K-V-A-E-K-L-R-E-A-F-NH2 (SEQ ID NO: 81)
Ac-E-W-L-R-A-F-Y-E-K-V-A-E-K-L-R-E-A-F-NH2 (SEQ ID NO: 82)
Ac-D-W-L-R-A-F-Y-D-R-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 83)
Ac-E-W-L-R-A-F-Y-E-R-V-A-E-K-L-K-E-A-F-NH2 (SEQ ID NO: 84)
Ac-D-W-L-K-A-F-Y-D-K-V-A-E-R-L-R-E-A-F-NH2 (SEQ ID NO: 85)
Ac-E-W-L-K-A-F-Y-E-K-V-A-E-R-L-R-E-A-F-NH2 (SEQ ID NO: 86)
Ac-D-W-L-R-A-F-Y-D-K-V-A-E-R-L-K-E-A-F-NH2 (SEQ ID NO: 87)
Ac-E-W-L-R-A-F-Y-E-K-V-A-E-R-L-K-E-A-F-NH2 (SEQ ID NO: 88)
D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-P-D-W
L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ ID NO: 89)
D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-P-D-W
L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F (SEQ ID NO: 90)
D-W-F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-P-D-W
F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ ID NO: 91)
D-K-L-K-A-F-Y-D-K-V-F-E-W-A-K-E-A-F-P-D-K
L-K-A-F-Y-D-K-V-F-E-W-L-K-E-A-F (SEQ ID NO: 92)
D-K-W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L-P-D-K
W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L (SEQ ID NO: 93)
D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-P-D-W
F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO: 94)
D-W-L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F-P-D-W
L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F (SEQ ID NO: 95)
D-W-L-K-A-F-Y-D-K-F-A-E-K-F-K-E-F-F-P-D-W
L-K-A-F-Y-D-K-F-A-E-K-F-K-E-F-F (SEQ ID NO: 96)
Ac-E-W-F-K-A-F-Y-E-K-V-A-E-K-F-K-E-A-F-NH2  (SEQ ID NO: 97)
Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-NH2 (SEQ ID NO: 98)
Ac-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-NH2 (SEQ ID NO: 99)
Ac-F-K-A-F-Y-E-K-V-A-E-K-F-K-E-NH2 (SEQ ID NO: 100)
NMA-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-NH2 (SEQ ID NO: 101)
NMA-F-K-A-F-Y-E-K-V-A-E-K-F-K-E-NH2 (SEQ ID NO: 102)
NMA-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID
NO: 103)
NMA-E-W-F-K-A-F-Y-E-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 104)
NMA-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2 (SEQ ID NO: 105)
NMA-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-NH2 (SEQ ID NO: 106)
Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 107)
NMA-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 108)
Ac-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 109)
NMA-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 110)
Ac-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 111)
NMA-A-F-Y-D-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 112)
Ac-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 113)
NMA-A-F-Y-E-K-V-F-E-K-F-K-E-F-F-NH2 (SEQ ID NO: 114)
Ac-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-NH2 (SEQ ID NO: 115)
NMA-D-W-L-K-A-F-Y-D-K-V-F-E-K-F-NH2 (SEQ ID NO: 116)
Ac-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-NH2 (SEQ ID NO: 117)
NMA-E-W-L-K-A-F-Y-E-K-V-F-E-K-F-NH2 (SEQ ID NO: 118)
Ac-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-NH2 (SEQ ID NO: 119)
NMA-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-NH2 (SEQ ID NO: 120)
Ac-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-NH2 (SEQ ID NO: 121)
NMA-L-K-A-F-Y-E-K-V-F-E-K-F-K-E-NH2 (SEQ ID NO: 122)
*Linkers are underlined; NMA is N-Methyl Anthranilyl
In certain aspects, the peptides include variations of 4F (D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO:16) in Table 2), also known as L-4F, where all residues are L form amino acids) or D-4F where one or more residues are D form amino acids). In any of the peptides described herein, the C-terminus, and/or N-terminus, and/or internal residues can be blocked with one or more blocking groups as described herein.
While various peptides of Table 2, are illustrated with an acetyl group or an N-methylanthranilyl group protecting the amino terminus and an amide group protecting the carboxyl terminus, any of these protecting groups may be eliminated and/or substituted with another protecting group as described herein. The peptides can comprise one or more D-form amino acids as described herein. In certain aspects, every amino acid (e.g., every enantiomeric amino acid) of the peptides of Table 2 is a D-form amino acid.
It is also noted that Table 2 is not fully inclusive. Using the teachings provided herein, other suitable class A amphipathic helical peptides can routinely be produced (e.g., by conservative or semi-conservative substitutions (e.g., D replaced by E), extensions, deletions, and the like). Thus, for example, one embodiment utilizes truncations of any one or more of peptides shown herein (e.g., peptides identified as 2F, 3F, 3F14, 4F, 5F, 6F, or 7F—in Table 2). Thus, for example, A-F-Y-D-K-V-A-E-K-L-K-E-A-F (amino acids 5-18 of SEQ ID NO:5) illustrates a peptide comprising 14 amino acids from the C-terminus of 18A comprising one or more D amino acids, while others illustrate other truncations.
Longer peptides are also suitable. Such longer peptides may entirely form a class A amphipathic helix, or the class A amphipathic helix (helices) can form one or more domains of the peptide. In addition, this invention contemplates multimeric versions of the peptides (e.g., concatamers). Thus, for example, the peptides illustrated herein can be coupled together (directly or through a linker (e.g., a carbon linker, or one or more amino acids) with one or more intervening amino acids). Illustrative polymeric peptides include 18A-Pro-18A and the peptides in the following table (Table 2B), in certain embodiments comprising one or more D amino acids, more preferably with every amino acid a D amino acid as described herein and/or having one or both termini protected.
TABLE 2B
Multimeric peptides.
Amino Acid Sequence
D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-P-D-W
L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F 
(SEQ ID NO: 90)
D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F-P-D-W
L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F 
(SEQ ID NO: 91)
D-W-F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F-P-D-W
F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F 
(SEQ ID NO: 92)
D-K-L-K-A-F-Y-D-K-V-F-E-W-A-K-E-A-F-P-D-K
L-K-A-F-Y-D-K-V-F-E-W-L-K-E-A-F (SEQ ID
NO: 93)
D-K-W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L-P-D-K
W-K-A-V-Y-D-K-F-A-E-A-F-K-E-F-L 
(SEQ ID NO: 94)
D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-P-D-W
F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F 
(SEQ ID NO: 95)
D-W-L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F-P-D-W
L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F
(SEQ ID NO: 96)
D-W-L-K-A-F-Y-D-K-F-A-E-K-F-K-E-F-F-P-D-W
L-K-A-F-Y-D-K-F-A-E-K-F-K-E-F-F 
(SEQ ID NO: 97)
b. Class A Amphipathic Helical Peptide Mimetics of apoA-I Having Aromatic or Aliphatic Residues in the Non-Polar Face.
Also disclosed are modified class A amphipathic helix peptides. Certain preferred peptides incorporate one or more aromatic residues at the center of the nonpolar face, e.g., 3FCπ, (as present in 4F), or with one or more aliphatic residues at the center of the nonpolar face, e.g., 3FIπ, see, e.g., Table 3. Without being bound to a particular theory, the central aromatic residues on the nonpolar face of the peptide 3FCπ, due to the presence of π electrons at the center of the nonpolar face can allow water molecules to penetrate near the hydrophobic lipid alkyl chains of the peptide-lipid complex, which in turn would enable the entry of reactive oxygen species (such as lipid hydroperoxides) shielding them from the cell surface. The peptides with aliphatic residues at the center of the nonpolar face, e.g., 3FIπ, can act similarly but not quite as effectively as 3FCπ.
In one aspect, the peptides can convert pro-inflammatory HDL to anti-inflammatory HDL or make anti-inflammatory HDL more anti-inflammatory, and/or decrease LDL-induced monocyte chemotactic activity generated by artery wall cells equal to or greater than D4F or other peptides shown in Table 2.
TABLE 3
Modified class A peptides.
Name Sequence
(3Fcn) Ac-DKWKAVYDKFAEAFKEFL-NH2 (SEQ ID NO: 123)
(3F1n) Ac-DKLKAFYDKVFEWAKEAF-NH2 (SEQ ID NO: 124)
c. Other Class A and Some Class Y Amphipathic Helical Peptides.
Class A amphipathic helical peptides that have an amino acid composition identical to one or more of the class A amphipathic helical peptides described above. Thus, for example, in certain embodiments this invention contemplates peptides having an amino acid composition identical to 4F. Thus, in certain embodiments, this invention includes active agents that comprise a peptide that consists of 18 amino acids, where the 18 amino acids consist of 3 alanines (A), 2 aspartates (D), 2 glutamates (E), 4 phenylalanines (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W), and 1 tyrosine (Y); and where the peptide forms a class A amphipathic helix; and protects a phospholipid against oxidation by an oxidizing agent. In various embodiments, the peptides comprise least one “D” amino acid residue; and in certain embodiments, the peptides comprise all “D: form amino acid residues. A variety of such peptides are illustrated in Table 4. Reverse (retro-), inverse, retro-inverso-, and circularly permuted forms of these peptides are also contemplated. Table 4 provides the sequences and identifier names for representative 18 amino acid length class A amphipathic helical peptides with the amino acid composition comprising 3 alanines (A), 2 aspartates (D), 2 glutamates (E), 4 phenylalanines (F), 4 lysines (K), 1 valine (V), 1 tryptophan (W), and 1 tyrosine (Y).
TABLE 4
18 amino acid length class A amphipathic helical
peptides.
Name Sequence
[Switch D-E]-4F analogs
[Switch D-E]-1-4F Ac- E WFKAFY E KVA D KFK D AF-NH2
(SEQ ID NO: 125)
[Switch D-E]-2-4F Ac- E WFKAFYDKVADKFK E AF-NH2
(SEQ ID NO: 126)
[Switch D-E]-3-4F Ac-DWFKAFY E KVA D KFKEAF-NH2
(SEQ ID NO: 127)
[Switch D-E]-4-4F Ac-DWFKAFY E KVAEKFK D AF-NH2
(SEQ ID NO: 128)
[W-2, F-3 positions reversed]
4F-2 Ac-D FW KAFYDKVAEKFKEAF-NH2
(SEQ ID NO: 129)
[Switch D-E]-1-4F-2 Ac- E FWKAFY E KVA D KFK D AF-NH2
(SEQ ID NO: 130)
[Switch D-E]-2-4F-2 Ac- E FWKAFYDKVADKFK E AF-NH2
(SEQ ID NO: 131)
[Switch D-E]-3-4F-2 Ac-DFWKAFY E KVA D KFKEAF-NH2
(SEQ ID NO: 132)
[Switch D-E]-4-4F-2 Ac-DFWKAFY E KVAEKFK D AF-NH2
(SEQ ID NO: 133)
[F-6 and Y-7 positions switched]
4F-3 Ac-DWFKAYFDKVAEKFKEAF-NH2
(SEQ ID NO: 134)
[Switch D-E]-1-4F-5 Ac-EWFKAYFEKVADKFKDAF-NH2
(SEQ ID NO: 135)
[Switch D-E]-2-4F-5 Ac-EWFKAYFDKVADKFKEAF-NH2
(SEQ ID NO: 136)
[Switch D-E]-3-4F-5 Ac-DWFKAYFEKVADKFKEAF-NH2
(SEQ ID NO: 137)
[Switch D-E]-4-4F-5 Ac-DWFKAYFEKVAEKFKDAF-NH2
(SEQ ID NO: 138)
[Y-l and 10V positions switched]
4F-4 Ac-DWFKAFVDKYAEKFKEAF-NH2
(SEQ ID NO: 139)
[Switch D-E]-1-4F-4 Ac- E WFKAFV E KYA D KFK D AF-NH2
(SEQ ID NO:140)
[Switch D-E]-2-4F-4 Ac- E WFKAFVDKYADKFK E AF-NH2
(SEQ ID NO: 141)
[Switch D-E]-3-4F-4 Ac-DWFKAFV E KYA D KFKEAF-NH2
(SEQ ID NO: 142)
[Switch D-E]-4-4F Ac-DWFKAFV E KYAEKFK D AF-NH2
(SEQ ID NO: 143)
[V-10 and A-11 switched]
4-F-5 Ac-DWFKAFYDK AV EKFKEAF-NH2
(SEQ ID NO: 144)
[Switch D-E]-1-4F-5 Ac- E WFKAFY E KAV D KFK D AF-NH2
(SEQ ID NO: 145)
[Switch D-E]-2-4F-5 Ac- E WFKAFYDKAVDKFK E AF-NH2
(SEQ ID NO: 146)
[Switch D-E]-3-4F-5 Ac-DWFKAFY E KAV D KFKEAF-NH2
(SEQ ID NO: 147)
[Switch D-E]-4-4F-5 Ac-DWFKAFY E KAVEKFK D AF-NH2
(SEQ ID NO: 148)
[A-11 and F-14 switched]
4F-6 Ac-DWFKAFYDKV F EK A KEAF-NH2
(SEQ ID NO: 149)
[Switch D-E]-1-4F-6 Ac- E WFKAFY E KVF D KAK D AF-NH2
(SEQ ID NO: 150)
[Switch D-E]-2-4F-6 Ac- E WFKAFYDKVFDKAK E AF-NH2
(SEQ ID NO: 151)
[Switch D-E]-3-4F-6 Ac-DWFKAFY E KVF D KAKEAF-NH2
(SEQ ID NO: 152)
[Switch D-E]-4-4F-6 Ac-DWFKAFY E KVFEKAK D AF-NH2
(SEQ ID NO: 153)
[F-14 and A-17 switched]
4F-7 Ac-DWFKAFYDKVAEK A KE F F-NH2
(SEQ ID NO: 154)
[Switch D-E]-1-4F-7 Ac- E WFKAFY E KVA D KAK D FF-NH2
(SEQ ID NO: 155)
[Switch D-E]-2-4F-7 Ac- E WFKAFYDKVADKAK E FF-NH2
(SEQ ID NO: 156)
[Switch D-E]-3-4F-7 Ac-DWFKAFY E KVA D KAKEFF-NH2
(SEQ ID NO: 157)
[Switch D-E]-4-4F-7 Ac-DWFKAFY E KVAEKAK D FF-NH2
(SEQ ID NO: 158)
[A-17 and F-18 switched]
4F-8 Ac-DWFKAFYDKVAEKFKE FA -NH2
(SEQ ID NO: 159)
[Switch D-E]-1-4F-8 Ac- E WFKAFY E KVA D KFK D FA-NH2
(SEQ ID NO: 160)
[Switch D-E]-2-4F-8 Ac- E WFKAFYDKVADKFK E FA-NH2
(SEQ ID NO: 161)
[Switch D-E]-3-4F-8 Ac-DWFKAFY E KVA D KFKEFA-NH2
(SEQ ID NO: 162)
[Switch D-E]-4-4F-8 Ac-DWFKAFY E KVAEKFK D FA-NH2
(SEQ ID NO: 163)
[W-2 and A-17 switched]
4F-9 Ac-D A FKAFYDKVAEKFKE W F-NH2
(SEQ ID NO: 164)
[Switch D-E]-1-4F-9 Ac- E AFKAFY E KVA D KFK D WF-NH2
(SEQ ID NO: 165)
[Switch D-E]-2-4F-9 Ac- E AFKAFYDKVADKFK E WF-NH2
(SEQ ID NO: 166)
[Switch D-E]-3 4F-9 Ac-DAFKAFY E KVA D KFKEWF-NH2
(SEQ ID NO: 167)
[Switch D-E]-4-4F-9 Ac-DAFKAFY E KVAEKFK D WF-NH2
(SEQ ID NO: 168)
[W-2 and A-11 switched]
4F-10 Ac-D A FKAFYDKV W EKFKEAF-NH2
(SEQ ID NO: 169)
[Switch D-E]-1-4F-10 Ac- E AFKAFY E KVW D KFK D AF-NH2
(SEQ ID NO: 170)
[Switch D-E]-2-4F-10 Ac- E AFKAFYDKVWDKFK E AF-NH2
(SEQ ID NO: 171)
[Switch D-E]-3-4F-10 Ac-DAFKAFY E KVW D KFKEAF-NH2
(SEQ ID NO: 172)
[Switch D-E]-4-4F-10 Ac-DAFKAFY E KVWEKFK D AF-NH2
(SEQ ID NO: 173)
[W-2 and Y-7 switched]
4F-11 Ac-D Y FKAF W DKVAEKFKEAF-NH2
(SEQ ID NO: 174)
[Switch D-E]-1-4F-11 Ac- E YFKAFW E KVA D KFK D AF-NH2
(SEQ ID NO: 175)
[Switch D-E]-2-4F-11 Ac- E YFKAFWDKVADKFK E AF-NH2
(SEQ ID NO: 176)
[Switch D-E]-3-4F-11 Ac-DYFKAFW E KVA D KFKEAF-NH2
(SEQ ID NO: 177)
[Switch D-E]-4-4F-11 Ac-DYFKAFW E KVAEKFK D AF-NH2
(SEQ ID NO: 178)
[F-3 and A-17 switched]
4F-12 Ac-DW A KAFYDKVAEKFKE F F-NH2
(SEQ ID NO: 179)
[Switch D-E]-1-4F-12 Ac- E WAKAFY E KVA D KFK D FF-NH2
(SEQ ID NO: 180)
[Switch D-E]-2-4F-12 Ac- E WAKAFYDKVADKFK E FF-NH2
(SEQ ID NO: 181)
[Switch D-E]-3-4F-12 Ac-DWAKAFY E KVA D KFKEFF-NH2
(SEQ ID NO: 182)
[Switch D-E]-4-4F-12 Ac-DWAKAFY E KVAEKFK D FF-NH2
(SEQ ID NO: 183)
[F-6 and A-17 switched]
4F-13 Ac-DWFKA A YDKVAEKFKE F F-NH2
(SEQ ID NO: 184)
[Switch D-E]-1-4F-13 Ac- E WFKAAY E KVA D KFK D FF-NH2
(SEQ ID NO: 185)
[Switch D-E]-2-4F-13 Ac- E WFKAAYDKVADKFK E FF-NH2
(SEQ ID NO: 186)
[Switch D-E]-3-4F-13 Ac-DWFKAAY E KVA D KFKEFF-NH2
(SEQ ID NO: 187)
[Switch D-E]-4-4F-13 Ac-DWFKAAY E KVAEKFK D FF-NH2
(SEQ I DNO: 188)
[Y-7 and A-17 switched
4F-14 Ac-DWFKAF A DKVAEKFKE Y F-NH2
(SEQ ID NO: 189)
[Switch D-E]-1-4F-14 Ac- E WFKAFA E KVA D KFK D YF-NH2
(SEQ ID NO: 190)
[Switch D-E]-2-4F-14 Ac- E WFKAFADKVADKFK E YF-NH2
(SEQ ID NO: 191)
[Switch D-E]-3-4F-14 Ac-DWFKAFA E KVA D KFKEYF-NH2
(SEQ ID NO: 192)
[Switch D-E]-4-4F Ac-DWFKAFA E KVAEKFK D YF-NH2
(SEQ ID NO: 193)
[V-10 and A-17 switched]
4F-15 Ac-DWFKAFYDK A AEKFKE V F-NH2
(SEQ ID NO: 194)
[Switch D-E]-1-4F-15 Ac- E WFKAFY E KAA D KFK D VF-NH2
(SEQ ID NO: 195)
[Switch D-E]-2-4F-15 Ac- E WFKAFYDKAADKFK E VF-NH2
(SEQ ID NO: 196)
[Switch D-E]-3-4F-15 Ac-DWFKAFY E KAA D KFKEVF-NH2
(SEQ ID NO: 197)
[Switch D-E]-4-4F-15 Ac-DWFKAFY E KAAEKFK D VF-NH2
(SEQ ID NO: 198)
[F3 and Y-7 switched]
4F-16 Ac-DW Y KAF F DKVAEKFKEAF-NH2
(SEQ ID NO: 199)
[Switch D-E]-1-4F-16 Ac- E WYKAFF E KVA D KFK D AF-NH2
(SEQ ID NO: 200)
[Switch D-E]-2-4F-16 Ac- E WYKAFFDKVADKFK E AF-NH2
(SEQ ID NO: 201)
[Switch D -E]-3-4F-16 Ac-DWYKAFF E KVA D KFKEAF-NH2
(SEQ ID NO: 202)
[Switch D-E]-4-4F-16 Ac-DWYKAFF E KVAEKFK D AF-NH2
(SEQ ID NO: 203)
[F-3 and V-10 switched]
4F-17 Ac-DW V KAFYDK F AEKFKEAF-NH2
(SEQ ID NO: 204)
[Switch D-E]-1-4F-17 Ac- E WVKAFY E KFA D KFK D AF-NH2
(SEQ ID NO: 205)
[Switch D-E]-2-4F-17 Ac- E WVKAFYDKFADKFK E AF-NH2
(SEQ ID NO: 206)
[Switch D-E]-3-4F-17 Ac-DWVKAFY E KFA D KFKEAF-NH2
(SEQ ID NO: 207)
[Switch D-E]-4-4F-17 Ac-DWVKAFY E KFAEKFK D AF-NH2
(SEQ ID NO: 208)
[Y-7 and F-14 switched]
4F-18 Ac-DWFKA F FDKVAEK Y KEAF-NH2
(SEQ ID NO: 209)
[Switch D-E]-1-4F-18 Ac- E WFKAFF E KVA D KYK D AF-NH2
(SEQ ID NO: 210)
[Switch D-E]-2-4F-18 Ac- E WFKAFFDKVADKYK E AF-NH2
(SEQ ID NO: 211)
[Switch D-E]-3-4F-18 Ac-DWFKAFF E KVA D KYKEAF-NH2
(SEQ ID NO: 212)
[Switch D-E]-3-4F-18 Ac-DWFKAFF E KVA D KYKEAF-NH2
(SEQ ID NO: 213)
[Y-7 and F-18 switched]
4F-19 Ac-DWFKAF F DKVAEKFKEA Y -NH2
(SEQ ID NO: 214)
[Switch D-E]-1-4F-19 Ac- E WFKAFF E KVA D KFK D AY-NH2
(SEQ ID NO: 215)
[Switch D-E]-2-4F-19 Ac- E WFKAFFDKVADKFK E AY-NH2
(SEQ ID NO: 216)
[Switch D-E]-3-4F-19 Ac-DWFKAFF E KVA D KFKEAY-NH2
(SEQ ID NO: 217)
[Switch D-E]-4-4F-19 Ac-DWFKAFF E KVAEKFK D AY-NH2
(SEQ ID NO: 218)
[V-10 and F-18 switched]
4F-20 Ac-DWFKAFYDK F AEKFKEA V -NH2
(SEQ ID NO: 219)
[Switch D-E]-1-4F-20 Ac- E WFKAFY E KFA D KFK D AV-NH2
(SEQ ID NO: 220)
[Switch D-E]-2-4F-20 Ac- E WFKAFYDKFADKFK E AV-NH2
(SEQ ID NO: 221)
[Switch D-E]-3-4F-20 Ac-DWFKAFY E KFA D KFKEAV-NH2
(SEQ ID NO: 222)
[Switch D-E]-4-4F-20 Ac-DWFKAFY E KFAEKFK D AV-NH2
(SEQ ID NO: 223)
[W-2 and K13 switched]
4F-21 Ac-D K FKAFYDKVAEKF W EAF-NH2
(SEQ ID NO: 224)
[Switch D-E]-1-4F-21 Ac- E KFKAFY E KVA D KFW D AF-NH2
(SEQ ID NO: 225)
[Switch D-E]-2-4F-21 Ac- E KFKAFYDKVADKFW E AF-NH2
(SEQ ID NO: 226)
[Switch D-E]-3-4F-21 Ac-DKFKAFY E KVA D KFWEAF-NH2
(SEQ ID NO: 227)
[Switch D-E]-4-4F-21 Ac-DKFKAFY E KVAEKFW D AF-NH2
(SEQ ID NO: 228)
[W-3, F-13 and K-2 4F]
4F-22 Ac-D KW KAFYDKVAEKF F EAF-NH2
(SEQ ID NO :229)
[Switch D-E]-1-4F-22 Ac- E KWKAFY E KVA D KFF D AF-NH2
(SEQ ID NO: 230)
[Switch D-E]-2-4F-22 Ac- E KWKAFYDKVADKFF E AF-NH2
(SEQ ID NO: 231)
[Switch D-E]-3-4F-22 Ac-DKWKAFY E KVA D KFFEAF-NH2
(SEQ ID NO: 232)
[Switch D-E]-4-4F-22 Ac-DKWKAFYEKVA E KFF D AF-NH2
(SEQ ID NO: 233)
[K-2, W10, V-13]
4F-23 Ac-DKF K AFYDK W AE V FKEAF-NH2
(SEQ ID NO: 234)
[Switch D-E]-4F analogs
[Switch D-E]-1-4F-23 Ac- E KFKAFY E KWA D VFK D AF-NH2
(SEQ ID NO: 235)
[Switch D-E]-2-4F-23 Ac- E KFKAFYDKWADVFK E AF-NH2
(SEQ ID NO: 236)
[Switch D-E]-3-4F-23 Ac-DKFKAFY E KWA D VFKEAF-NH2
(SEQ ID NO: 237)
[Switch D-E]-4-4F-23 Ac-DKFKAFY E KWAEVFK D AF-NH2
(SEQ ID NO: 238)
[K-2, F-13, W-14 4F]
4F-24 Ac-D K FKAFYDKVAE FW KEAF-NH2
(SEQ ID NO: 239)
[Switch D-E]-4F analogs
[Switch D-E]-1-4F-24 Ac- E KFKAFY E KVA D FWK D AF-NH2
(SEQ ID NO :240)
[Switch D-E]-2-4F-24 Ac- E KF1CAFYDKVADFWK E AF-
NH2 (SEQ ID NO: 241)
[Switch D-E]-3-4F-24 Ac-DKFKAFY E KVA D FWKEAF-NH2
(SEQ ID NO: 242)
[Switch D-E]-4-4F-24 Ac-DKFKAFY E KVAEFWK D AF-NH2
(SEQ ID NO: 243)
Reverse 4F analogs
Rev-4F Ac-FAEKFKEAVKDYFAKFWD-NH2
(SEQ ID NO: 244)
[Switch D-E]-1-Rev-4F Ac-FA D KFK D AVK E YFAKFW E -NH2
(SEQ ID NO: 245)
[Switch D-E]-2-Rev-4F Ac-FA D KFKEAVKDYFAKFW E -NH2
(SEQ ID NO: 246)
[Switch D-E]-3-Rev-4F Ac-FAEKFK D AVKEYFAKFWD-NH2
(SEQ ID NO: 247)
[Switch D-E]-4-Rev-4F Ac-FAEKFK D AVKDYFAKFW E -NH2
(SEQ ID NO: 248)
[A-2 and W-17 switched]
Rev-4F -1 Ac-F W EKFKEAVKDYFAKF A D-NH2
(SEQ ID NO: 249)
[Switch D-E]-1-Rev-4F-1 Ac-FW D KFK D AVK E YFAKFA E -NH2
(SEQ ID NO: 250)
[Switch D-E]-2-Rev-4F-1 Ac-FA D KFKEAVKDYFAKFW E -NH2
(SEQ ID NO: 251)
[Switch D-E]-3-Rev-4F-1 Ac-FAEKFK D AVK E YFAKFWD-NH2
(SEQ ID NO: 252)
[Switch D-E]-4-Rev-4F-1 Ac-FAEKFK D AVKDYFAKFW E -NH2
(SEQ ID NO: 253)
[Switch A-2 and F-16]
Rev-4F-2 Ac-F F EKFKEAVKDYFAK A WD-NH2
(SEQ ID NO :254)
[Switch D-E]-1-Rev-4F-2 Ac-FF D KFK D AVK E YFAKAW E -NH2
(SEQ ID NO: 255)
[Switch D-E]-2-Rev-4F-2 Ac-FF D KFKEAVKDYFAKAW E -NH2
(SEQ ID NO: 256)
[Switch D-E]-3-Rev-4F-2 Ac-FFEKFK D AVK E YFAKAWD-NH2
(SEQ ID NO: 257)
[Switch D-E]-4-Rev-4F-2 Ac-FFEKFK D AVKDYFAKAW E -NH2
(SEQ ID NO: 258)
[switch F-5 and A-8]
Rev-4F-3 Ac-FAEK A KE F VKDYFAKFWD-NH2
(SEQ ID NO: 259)
[Switch D-E]-1-Rev-4F-3 Ac-FA D KAK D FVK E YFAKFW E -NH2
(SEQ ID NO: 260)
[Switch D-E]-2-Rev-4F-3 Ac-FA D KAKEFVKDYFAKFW E -NH2
(SEQ ID NO: 261)
[Switch D-E]-3-Rev-4F-3 Ac-FAEKAK D FVK E YFAKFWD-NH2
(SEQ ID NO: 262)
[Switch D-E]-4-Rev-4F-3 Ac-FAEKAK D FVKDYFAKFW E -NH2
(SE0 ID NO: 263)
[Switch A-8 and V9]
Rev-4F-4 Ac-FAEKFKE VA KDYFAKFWD-NH2
(SEQ ID NO: 264)
[Switch D-E]-1-Rev-4F-4 Ac-FA D KFK D VAK E YFAKFW E -NH2
(SEQ ID NO: 265)
[Switch D-E]-2-Rev-4F-4 Ac-FA D KFKEVAKDYFAKFW E -NH2
(SEQ ID NO: 266)
[Switch D-E]-3-Rev-4F-4 Ac-FAEKFK D VAK E YFAKFWD-NH2
(SEQ ID NO: 267)
[Switch D-E]-4-Rev-4F-4 Ac-FAEKFK D VAKDYFAKFW E -NH2
(SEQ ID NO: 268)
[Switch V-9 to Y-12]
Rev-4F-5 Ac-FAEKFKEA Y KD V FAKFWD-NH2
(SEQ ID NO: 267)
[Switch D-E]-1-Rev-4F-5 Ac-FA D KFK D AYK E VFAKFW E -NH2
(SEQ ID NO: 268)
[Switch D-E]-2-Rev-4F-5 Ac-FA D KFKEAYKDVFAKFW E -NH2
(SEQ ID NO: 269)
[Switch D-E]-3-Rev-4F-5 Ac-FAEKFK D AYK E VFAKFWD-NH2
(SEQ ID NO: 270)
[Switch D-E]-4-Rev-4F-5 Ac-FAEKFK D AYKDVFAKFW E -NH2
(SEQ ID NO: 271)
[Switch Y-12 and F-13]
Rev-4F-6 Ac-FAEKFKEAVKD FY AKFWD-NH2
(SEQ ID NO: 272)
[Switch D-E]-1-Rev-4F-6 Ac-FA D KFK D AVKEFYAKFW E -NH2
(SEQ ID NO: 273)
[Switch D-E]-2-Rev-4F-6 Ac-FA D KFKEAVKDFYAKFW E -NH2
(SEQ ID NO: 274)
[Switch D-E]-3-Rev-4F-6 Ac-FAEKFK D AVK E FYAKFWD-NH2
(SEQ ID NO: 275)
[Switch D-E]-4-Rev-4F-6 Ac-FAEKFK D AVKDFYAKFW E -NH2
(SEQ ID NO: 276)
[Switch K-6 and W-17]
Rev-4F-7 Ac-FAEKF W EAVKDYFAKF K D-NH2
(SEQ ID NO: 277)
[Switch D-E]-1-Rev-4F-7 Ac-FA D KFW D AVK E YFAKFK E -NH2
(SEQ ID NO: 278)
[Switch D-E]-2-Rev-4F-7 Ac-FA D KFWEAVKDYFAKFK E -NH2
(SEQ ID NO: 279)
[Switch D-E]-3-Rev-4F-7 Ac-FAEKFW D AVK E YFAKFKD-NH2
(SEQ ID NO: 280)
[Switch D-E]-4-Rev-4F-7 Ac-FAEKFW D AVKDYFAKFK E -NH2
(SEQ ID NO: 281)
[Switch F-1 and A-2]
Rev-4F-8 Ac- A F EKFKEAVKDYFAKFWD-NH2
(SEQ ID NO: 282)
[Switch D-E]-1-Rev-4F-8 Ac-AF D KFK D AVK E YFAKFW E -NH2
(SEQ ID NO: 283)
[Switch D-E]-2-Rev-4F-8 Ac-AF D KFKEAVKDYFAKFW E -NH2
(SEQ ID NO: 284)
[Switch D-E]-3-Rev-4F-8 Ac-AFEKFK D AVK E YFAKFWD-NH2
(SEQ ID NO: 285)
[Switch D-E]-4-Rev-4F-8 Ac-AFEKFK D AVKDYFAKFW E -NH2
(SEQ ID NO: 286)
[F-1 and V-9 are switched]
Rev-F-9 Ac- V AEKFKEA F KDYFAKFWD-NH2
(SEQ ID NO: 287)
[Switch D-E]-1-Rev-4F-9 Ac-VA D KFK D AFK E YFAKFW E -NH2
(SEQ ID NO: 288)
[Switch D-E]-2-Rev-4F-9 Ac-VA D KFKEAFKDYFAKFW E -NH2
(SEQ ID NO: 289)
[Switch D-E]-3-Rev-4F-9 Ac-VAEKFK D AFK E YFAKFWD-NH2
(SEQ ID NO: 290)
[Switch D-E]-4-Rev-4F-9 Ac-VAEKFK D AFKDYFAKFWE-NH2
(SEQ ID NO: 291)
[F-1 and Y-12 are switched]
Rev-4F -10 Ac- Y AEKFKEAVKD F FAKFWD-NH2
(SEQ ID NO: 292)
[Switch D-E]-1-Rev-4F-10 Ac-YA D KFK D AVK E FFAKFW E -NH2
(SEQ ID NO: 293)
[Switch D-E]-2-Rev-4F-10 Ac-YA D KFKEAVKDFFAKFW E -NH2
(SEQ ID NO: 294)
[Switch D-E]-3-Rev-4F-10 Ac-YAEKFK D AVK E FFAKFWD-NH2
(SEQ ID NO: 295)
[Switch D-E]-4-Rev-4F-10 Ac-YAEKFK D AVKDFFAKFW E -NH2
(SEQ ID NO: 296)
[F-1 and A-8 are switched]
Rev-4F-11 Ac- A AEKFKE F VKDYFAKFWD-NH2
(SEQ ID NO: 297)
[Switch D-E]-1-Rev-4F-11 Ac-AA D KFK D FVK E YFAKFW E -NH2
(SEQ ID NO: 298)
[Switch D-E]-2-Rev-4F-11 Ac-AA D KFKEFVKDYFAKFW E -NH2
(SEQ ID NO :299)
[Switch D-E]-3-Rev-4F-11 Ac-AAEKFK D FVK E YFAKFWD-NH2
(SEQ ID NO: 300)
Switch D-E]-4-Rev-4F-11 Ac-AAEKFKDFVK D YFAKFW E -NH2
(SEQ ID NO: 301)
[A-2 and F-5 are switched]
Rev-4F -12 Ac-F F EK A KEAVKDYFAKFWD-NH2
(SEQ ID NO: 302)
[Switch D-E]-1-Rev-4F-12 Ac-FF D KAK D AVK E YFAKFW E -NH2
(SEQ ID NO: 303)
[Switch D-E]-2-Rev-4F-12 Ac-FF D KAKEAVKDYFAKFW E -NH2
(SEQ ID NO: 304)
[Switch D-E]-3-Rev-4F-12 Ac-141-EKAK D AVK E YFAKFWD-
NH2 (SEQ ID NO: 305)
[Switch D-E]-4-Rev-4F-12 Ac-1-1-EKAK D AVKDYFAKFW E -
NH2 (SEQ ID NO: 306)
[A-2 and Y12 are switched
Rev-4F -13 Ac-F Y EKFKEAVKD A FAKFWD-NH2
(SEQ ID NO: 307)
[Switch D-E]-1-Rev-4F-13 Ac-FY D KFK D AVK E AFAKFW E -NH2
(SEQ ID NO: 308)
[Switch D-E]-2-Rev-4F-13 Ac-FY D KFKEAVKDAFAKFW E -NH2
(SEQ ID NO: 309)
[Switch D-E]-3-Rev-4F-13 Ac-FYEKFK D AVK E AFAKFWD-NH2
(SEQ ID NO: 310)
[Switch D-E]-4-Rev-4F-13 Ac-FYEKFK D AVKDAFAKFW E -NH2
(SEQ ID NO: 311)
[A-2 and V-9 are switched]
Rev-4F -14 Ac-F V EKFKEA A KDYFAKFWD-NH2
(SEQ ID NO: 312)
[Switch D-E]-1-Rev-4F-14 Ac-FV D KFK D AAK E YFAKFW E -NH2
(SEQ ID NO: 313)
[Switch D-E]-2-Rev-4F-14 Ac-FV D KFKEAAKDYFAKFW E -NH2
(SEQ ID NO: 314)
[Switch D-E]-3-Rev-4F-14 Ac-FVEKFK D AAK E YFAKFWD-NH2
(SEQ ID NO: 315)
[Switch D-E]-4-Rev-4F-14 Ac-FVEKFK D AAKDYFAKFW E -NH2
(SEQ ID NO: 316)
[F-5 and Y-12 are switched]
Rev-4F -15 Ac-FAEK Y KEAVKD F FAKFWD-NH2
(SEQ ID NO: 317)
[Switch D-E]-1-Rev-4F-15 Ac-FA D KYK D AVK E FFAKFW E -NH2
(SEQ ID NO: 318)
[Switch D-E]-2-Rev-4F-15 Ac-FA D KYKEAVKDFFAKFW E -NH2
(SEQ ID NO: 319)
[Switch D-E]-3-Rev-4F-15 Ac-FAEKYK D AVK E FFAKFWD-NH2
(SEQ ID NO: 320)
[Switch D-E]-4-Rev-4F-15 Ac-FAEKYK D AVKDFFAKFW E -NH2
(SE0 ID NO: 321)
[F-5 and V-9 are switched]
Rev-4F -16 Ac-FAEK V KEA F KDYFAKFWD-NH2
(SEQ ID NO: 322)
[Switch D-E]-1-Rev-4F-16 Ac-FA D KVK D AFK E YFAKFW E -NH2
(SEQ ID NO: 323)
[Switch D-E]-2-Rev-4F-16 Ac-FA D KVKEAFKDYFAKFW E -NH2
(SEQ ID NO: 324)
[Switch D-E]-3-Rev-4F-16 Ac-FAEKVK D AFK E YFAKFWD-NH2
(SEQ ID NO: 325)
[Switch D-E]-4-Rev-4F-16 Ac-FAEKVK D AFKDYFAKFW E -NH2
(SEQ ID NO: 326)
[A-8 and Y-12 switched]
Rev-4F -17 Ac-FAEKFKE Y VKD A FAKFWD-NH2
(SEQ ID NO: 327)
[Switch D-E]-1-Rev-4F-17 Ac-FA D KFK D YVK E AFAKFW E -NH2
(SEQ ID NO: 328)
[Switch D-E]-2-Rev-4F-17 Ac-FA D KFKEYVKDAFAKFW E -NH2
(SEQ ID NO: 329)
[Switch D-E]-3-Rev-4F-17 Ac-FAEKFK D YVK E AFAKFWD-NH2
(SEQ ID NO: 330)
[Switch D-E]-4-Rev-4F-17 Ac-FAEKFK D YVKDAFAKFW E -NH2
(SEQ ID NO: 331)
[V-9 and F-13 are switched]
Rev-4F -18 Ac-FAEKFKEA F KDY V AKFWD-NH2
(SEQ ID NO: 332)
[Switch D-E]-1-Rev-4F-18 Ac-FA D KFK D AFK E YVAKFW E -NH2
(SEQ ID NO: 333)
[Switch D-E]-2-Rev-4F-18 Ac-FA D KFKEAFKDYVAKFW E -NH2
(SEQ ID NO: 334)
[Switch D-E]-3-Rev-4F-18 Ac-FAEKFK D AFK E YVAKFWD-NH2
(SEQ ID NO: 335)
[Switch D-E]-4-Rev-4F-18 Ac-FAEKFK D AFKDYVAKFW E -NH2
(SEQ ID NO: 336)
[V-9 and F-16 switched]
Rev-4F -19 Ac-FAEKFKEA F KDYFAK V WD-NH2
(SEQ ID NO: 337)
[Switch D-E]-1-Rev-4F-19 Ac-FA D KFK D AFK E YFAKVW E -NH2
(SEQ ID NO: 338)
[Switch D-E]-2-Rev-4F-19 Ac-FA D KFKEAFKDYFAKVW E -NH2
(SEQ ID NO: 339)
[Switch D-E]-3-Rev-4F-19 Ac-FAEKFK D AFK E YFAKVWD-NH2
(SEQ ID NO: 340)
Switch D-E]-4-Rev-4F-19 Ac-FAEKFK D AFKDYFAKVW E -NH2
(SEQ ID NO: 341)
[Y-12 and F-16 are switched
Rev-4F-20 Ac-FAEKFKEAVKD F FAK Y WD-NH2
(SEQ ID NO: 342)
[Switch D-E]-1-Rev-4F-20 Ac-FA D KFK D AVK E FFAKYW E -NH2
(SEQ ID NO: 343)
[Switch D-E]-2-Rev-4F-20 Ac-FA D KFKEAVKDFFAKYW E -NH2
(SEQ ID NO: 344)
[Switch D-E]-3-Rev-4F-20 Ac-FAEKFK D AVK E FFAKYWD-NH2
(SEQ ID NO: 345)
[Switch D-E]-4-Rev-4F-20 Ac-FAEKFK D AVKDFFAKYW E -NH2
(SEQ ID NO: 346)
[W-1, F-6 and K-17 Rev 4F]
Rev-4F -21 Ac- W AEKFFEAVKDYFAKF K D-NH2
(SEQ ID NO: 347)
[Switch D-E]-1-Rev-4F-7 Ac-WA D KFF D AVKEYFAKFK E -NH2
(SEQ ID NO: 348)
[Switch D-E]-2-Rev-4F-7 Ac-WA D KFFEAVKDYFAKFK E -NH2
(SEQ ID NO: 349)
[Switch D-E]-3-Rev-4F-7 Ac-WAEKFF D AVK E YFAKFKD-NH2
(SEQ ID NO: 350)
Switch D-E]-4-Rev-4F-7 Ac-WAEKFF D AVKDYFAKFK E -NH2
(SEQ ID NO: 351)
[W-5, F-6 and K-17 Rev-4F]
Rev-4F-22 Ac-FAEK WF EAVKDYFAKF K D-NH2
(SEQ ID NO: 352)
[Switch D-E]-1-Rev-4F-22 Ac-FA D KWF D AVK E YFAKFK E -NH2
(SEQ ID NO: 353)
[Switch D-E]-2-Rev-4F-22 Ac-FA D KWFEAVKDYFAKFK E -NH2
(SEQ ID NO: 354)
[Switch D-E]-3-Rev-4F-22 Ac-FAEKWF D AVK E YFAKFKD-NH2
(SEQ ID NO: 355)
[Switch D-E]-4-Rev-4F-22 Ac-FAEKWF D AVKDYFAKFK E -NH2
(SEQ ID NO: 356)
[V-6, W-9, K-17 Rev-4F]
Rev-4F-23 Ac-FAEKF V EA W KDYFAKF K D-NH2
(SEQ ID NO: 357)
[Switch D-E]-1-Rev-4F-23 Ac-FA D KFV D AWK E YFAKFK E -NH2
(SEQ ID NO: 358)
[Switch D-E]-2-Rev-4F-23 Ac-FA D KFVEAWKDYFAKFK E -NH2
(SEQ ID NO: 359)
[Switch D-E]-3-Rev-4F-23 Ac-FAEKFV D AWK E YFAKFKD-NH2
(SEQ ID NO: 360)
[Switch D-E]-4-Rev-4F-23 Ac-FAEKFV D AWKDYFAKFK E -NH2
(SEQ ID NO: 361)
[Y-2, A-4, W-12, K-17 Rev-4F]
Rev-4F-24 Ac-F Y EKF A EAVKD W FAKF K D-NH2
(SEQ ID NO: 362)
[Switch D-E]-1-Rev-4F-24 Ac-FY D KFA D AVK E WFAKFKE-NH2
(SEQ ID NO: 363)
[Switch D-E]-2-Rev-4F-24 Ac-FY D KFAEAVKDWFAKFK E -NH2
(SEQ ID NO: 364)
[Switch D-E]-3-Rev-4F-24 Ac-FYEKFA D AVK E WFAKFKD-NH2
(SEQ ID NO: 365)
[Switch D-E]-4-Rev-4F-24 Ac-FYEKFA D AVKDWFAKFK E -NH2
(SEQ ID NO: 366)
It is possible to readily identify biologically active and useful peptides. Thus, for example, the following peptides have been accurately identified as active: 3F1; 3F2; 4F the reverse (retro) forms thereof and the retro-inverso forms thereof. Lipid-associating peptides can comprise a peptide that is 18 amino acids in length and forms a class A amphipathic helix where the peptide has the amino acid composition 2 aspartates, 2 glutamates, 4 lysines, 1 tryptophan, 1 tyrosine, no more than one leucine, no more than 1 valine, no less than 1 and no more than 3 alanines, and with 3 to 6 amino acids from the group: phenylalanine, alpha-naphthalanine, beta-naphthalanine, histidine, and contains either 9 or 10 amino acids on the polar face in a helical wheel representation of the class A amphipathic helix including 4 amino acids with positive charge at neutral pH with two of the positively charged residues residing at the interface between the polar and non-polar faces and with two of the four positively charged residues on the polar face that are contiguous and on the non-polar face two of the amino acid residues from the group: phenylalanine, alpha-naphthalanine, beta-naphthalanine, histidine are also contiguous and if there are 4 or more amino acids from this group on the non-polar face there are also at least 2 residues from this group that are not contiguous. In some instances, all of the acidic amino acids are glutamic acid rather than having two aspartic acids and two glutamic acids. In some aspects, the lipid associating peptide can be 18A, wherein each of the acidic amino acids of 18A are Glu residues.
Certain class Y as well as class A amphipathic helical peptides are disclosed. Class Y amphipathic helical peptides are known to those of skill in the art (see, e.g., Segrest et al. (1992) J. Lipid Res. 33: 141-166; Oram and Heinecke (2005) Physiol Rev. 85: 1343-1372, and the like). These peptides include, but are not limited to, an 18 amino acid peptide that forms a class A amphipathic helix or a class Y amphipathic helix described by formula I:
(SEQ ID NO:  367)
D X X K Y X X D K X Y D K X K D Y X (I)

where the D's are independently Asp or Glu; the Ks are independently Lys or Arg; the Xs are independently Leu, nor Leu, Val, Ile, Trp, Phe, Tyr, β-Nal, or α-Nal and all X residues are on the non-polar face (e.g., when viewed in a helical wheel diagram) except for one that can be on the polar face between two K residues; the Y's are independently Ala, His, Ser, Gln, Asn, or Thr non-polar face (e.g., when viewed in a helical wheel diagram) and the Y's are independently one Ala on the polar face, one His, one Ser, one Gln one Asn, or one Thr on the polar face (e.g., when viewed in a helical wheel diagram), where no more than two K are be contiguous (e.g., when viewed in a helical wheel diagram); and where no more than 3 D's are contiguous (e.g., when viewed in a helical wheel diagram) and the fourth D is be separated from the other D's by a Y. Representative peptides of this kind which include peptides with histidine, and/or alpha- and/or beta-napthalanine are shown in Table 5. Reverse (retro-), inverse, retro-inverso-, and circularly permuted forms of these peptides are also contemplated.
TABLE 5
Class Y Amphipathic Helical Peptides.
Short Name Peptide Sequence
[A-5 > H]4F Ac-DWFKHFYDKVAEKFKEAF-NH2
(SEQ ID NO: 368)
[A-5 > H, D-E switched] 4F Ac-EWFKHFYEKVADKFKDAF-NH2
(SEQ ID NO: 369)
[A-5 > H, D-1 > E]4F Ac-EWFKHFYDKVAEKFKEAF-NH2
(SEQ ID NO: 370)
[A-5 > H, D-8 > E]4-F Ac-DWFKHFYEKVAEKFKEAF-NH2
(SEQ ID NO: 371)
[A-5 > H, E-12 > D]4F Ac-DWFKHFYDKVADKFKEAF-NH2
(SEQ ID NO: 372)
[A-5 > H, E-16 > D]4F Ac-DWFKHFYDKVAEKFKDAF-NH2
(SEQ ID NO: 373)
[F-3 > H, A-5 > F]-4F Ac-DWHKFFYDKVAEKFKEAF-NH2
(SEQ ID NO: 374)
[F-3 > H, A-5 > F, D-E switched]-4F Ac-EWHKFFYEKVADKFKDAF-NH2
(SEQ ID NO: 375)
[F-3 > H, A-5 > F, D-1 > E]-4F Ac-EWHKFFYDKVAEKFKEAF-NH2
(SEQ ID NO: 376)
[F-3 > H, A-5 > F, D-8 > E]-4F Ac-DWHKFFYEKVAEKFKEAF-NH2
(SEQ ID NO: 377)
[F-3 > H, A-5 > F, E- 12 > D]-4F Ac-DWHKFFYDKVADKFKEAF-NH2
(SEQ ID NO: 378)
[F-3 > H, A-5 > F, E-16 > D]-4F Ac-DWHKFFYDKVAEKFKDAF-NH2
(SEQ ID NO: 379)
[A-5 > F, F-6 > H]4F Ac-DWFKFHYDKVAEKFKEAF-NH2
(SEQ ID NO: 380)
[A-5 > F, F-6 > H, D-E switched]4F Ac-EWFKFHYEKVADKFKDAF-NH2
(SEQ ID NO: 381)
[[A-5 > F, F-6 > H, D- 1 > E]4F Ac-EWFKFHYDKVAEKFKEAF-NH2
(SEQ ID NO: 382)
[A-5 > F, F-6 > H, D-8 > E]4F Ac-DWFKFHYEKVAEKFKEAF-NH2
(SEQ ID NO: 383)
[A-5 > F, F-6 > H, E-12 > D]4F Ac-DWFKFHYDKVADKFKEAF-NH2
(SEQ ID NO: 384)
[A-5 > F, F-6 > H, E- 16 > D]4F Ac-DWFKFHYDKVAEKFKDAF-NH2
(SEQ ID NO: 385)
[A-5 > V, V-10 > H]4F Ac-DWFKVFYDKHAEKFKEAF-NH2
(SEQ ID NO: 386)
[A-5 > V, V-10 > H, D-E switched]4F Ac-EWFKVFYEKHADKFKDAF-NH2
(SEQ ID NO: 387)
[A-5 > V, V-10 > H, D-1 > E]4F Ac-EWFKVFYDKHAEKFKEAF-NH2
(SEQ ID NO: 388)
[A-5 > V, V-10 > H, D-8 > E]4F Ac-DWFKVFYEKHAEKFKEAF-NH2
(SEQ ID NO: 389)
[A-5 > V, V-10 > H, E-12 > D]4F Ac-DWFKVFYDKHADKFKEAF-NH2
(SEQ ID NO: 390)
[A-5 > V, V-10 > H, E16 > D]4F Ac-DWFKVFYDKHAEKFKDAF-NH2
(SEQ ID NO: 391)
[[A-17 > H]4F Ac-DWFKAFYDKVAEKFKEHF-NHA:
(SEQ ID NO: 392)
[A-17 > H, D-E switched]4F Ac-EWFKAFYEKVADKFKDHF-NH2
(SEQ ID NO: 393)
[[A-17 > H, D-1 > E]4F Ac-EWFKAFYDKVAEKFKEHF-NH2
(SEQ ID NO: 394)
[[A-17 > H, D-8 > E]4F Ac-DWFKAFYEKVAEKFKEHF-NH2
(SEQ ID NO: 395)
[[A-17 > H, E-12 > D]4F Ac-DWFKAFYDKVADKFKEHF-NH2
(SEQ ID NO: 396)
[[A-17 > H, E16 > D]4F Ac-DWFKAFYDKVAEKFKDHF-NH2
(SEQ ID NO: 397)
[A-17 > F, F-18 > H]4F Ac-DWFKAFYDKVAEKFKEFH-NH2
(SEQ ID NO: 398)
[A-17 > F, F-18 > H, D-E switched]4F Ac-EWFKAFYEKVADKFKDFH-NH2
(SEQ ID NO: 399)
[A-17 > F, F-18 > H, D-1 > E]-4F Ac-EWFKAFYDKVAEKFKEFH-NH2
(SEQ ID NO: 400)
[A-17 > F, F-18 > H]4F Ac-DWFKAFYDKVAEKFKEFH-NH2
(SEQ ID NO: 401)
[A-17 > F, F-18 > H, D-8 > E]-4F Ac-DWFKAFYEKVAEKFKEFH-NH2
(SEQ ID NO: 402)
[A-17 > F, F-18 > H, E-12 > D]4F Ac-DWFKAFYDKVAEKFKEFH-NH2
(SEQ ID NO: 403)
[A-17 > F, F-1 8 > H], E-16 > D]-4F Ac-DWFKAFYDKVAEKFKDFH-NH2(
(SEQ ID NO: 404)
Rev-4F Ac-FAEKFKEAVKDYFAKFWD-NH2
(SEQ ID NO: 405)
[A-2 > H]Rev4F Ac-FHEKFKEAVKDYFAKFWD-NH2
(SEQ ID NO: 406)
Rev-[A-2 > H, D > E]-4F Ac-FHEKFKEAVKEYFAKFWE-NH2
(SEQ ID NO: 407)
Rev-[A-2 > H, E > D]4F Ac-FHDKFKDAVKDYFAKFWD-NH2
(SEQ ID NO: 408)
[A-2 > H, D-E switched]Rev-4F Ac-FHDKFKDAVKEYFAKFWE-NH2
(SEQ ID NO: 409)
[A-2 > H, E-3 > D]Rev-4F Ac-FHDKFKEAVKDYFAKFWD-NH2
(SEQ ID NO: 410)
[A-2 > H, E-7 > D]Rev-4F Ac-FHEKFKDAVKDYFAKFWD-NH2
(SEQ ID NO: 411)
[A-2 > 2H, D-11 > E]Rev-4F Ac-FHEKFKEAVKEYFAKFWD-NH2
(SEQ ID NO: 412)
[A-2 > H, D-18 > E]Rev-4F Ac-FHEKFKEAVKDYFAKFWE-NH2
(SEQ ID NO: 413)
[F-1 > H, A-2 > F]Rev-4F Ac-HFEKFKEAVKDYFAKFWD-NH2
(SEQ ID NO: 414)
[F-1 > H, A-2 > F, D-E switched]Rev-4F Ac-HFDKFKDAVKEYFAKFWE-NH2
(SEQ ID NO: 415)
[F-1 > H, A-2 > F, D > E]Rev-4F Ac-HFEKFKEAVKEYFAKFWE-NH2
(SEQ ID NO: 416)
[F-1 > H, A-2 > F, E-3 > D]Rev-4F Ac-HFDKFKEAVKDYFAKFWD-NH2
(SEQ ID NO: 417)
[F-1 > H, A-2 > F, E-7 > D]Rev-4F Ac-HFEKFKDAVKDYFAKFWD-NH2
(SEQ ID NO: 418)
[F-1 > H, A-2 > F, D-11 > E]Rev-4F Ac-HFEKFKEAVKEYFAKFWD-NH2
(SEQ ID NO: 419)
[F-1 > H, A-2 > F, D-18 > E]Rev-4F Ac-HFEKFKEAVKDYFAKFWE-NH2
(SEQ ID NO: 420)
[A-2 > F, F-5 > H]Rev D-4F Ac-FFEKHKEAVKDYFAKFWD-NH2
(SEQ ID NO: 421)
[A-2 > F, F-5 > H, D-E switched] Ac-FFDKHKDAVKEYFAKFWE-NH2
Rev D-4F (SEQ ID NO: 422)
[A-2 > F, F-5 > H, D > E]Rev D-4F Ac-FFEKHKEAVKEYFAKFWE-NH2
(SEQ ID NO: 423)
[A-2 > F, F-5 > H, E > D]Rev D-4F [ Ac-FFDKHKDAVKDYFAKFWD-NH2
(SEQ ID NO: 424)
A-2 > F, F-5 > H, E-3 > D]Rev Ac-FFDKHKEAVKDYFAKFWD-NH2
(SEQ ID NO: 425)
D-4F [A-2 > F, F-5 > H, D-11 > E] Ac-FFEKHKEAVKEYFAKFWD-NH2
Rev D-4F (SEQ ID NO: 426)
[A-2 > F, F-5 > H, D-18 > E]Rev D-4F Ac-FFEKHKEAVKDYFAKFWE-NH2
(SEQ ID NO: 427)
[A-2 > V, V-9 > H]Rev D-4F Ac-FVEKFKEAHKDYFAKFWD-NH2
(SEQ ID NO: 428)
[A-2 > V, V-9 > H, D- E switched] Ac-FVDKFKDAHKEYFAKFWE-NH2
Rev D-4 (SEQ ID NO: 429)
[A-2 > V, V-9 > H, D > E]Rev D-4F Ac-FVEKFKEAHKEYFAKFWE-NH2
(SEQ ID NO: 430)
[A-2 > V, V-9 > H, E > D]Rev D-4F Ac-FVDKFKDAHKDYFAKFWD-NH2
(SEQ ID NO: 431)
[A-2 > V, V-9 > H, E-3 > D]Rev D-4F Ac-FVDKFKEAHKDYFAKFWD-NH2
(SEQ ID NO: 432)
[A-2 > V, V-9 > H, E-7 > D]Rev D-4F Ac-FVEKFKDAHKDYFAKFWD-NH2
(SEQ ID NO: 433)
[A-2 > V, V-9 > H, D-11 > E]Rev D-4F Ac-FVEKFKEAHKEYFAKFWD-NH2
(SEQ ID NO: 434)
[A-2 > V, V-9 > H, D-18 > E]Rev D-4F Ac-FVEKFKEAHKDYFAKFWE-NH2
(SEQ ID NO: 435)
[A-8 > H]Rev-4F Ac-FAEKFKEHVKDYFAKFWD-NH2
(SEQ ID NO: 436)
[A-8 > H, D-E switched]Rev-4F Ac-FADKFKDHVKEYFAKFWE-NH2
(SEQ ID NO: 437)
[A-8 > H, D > E]Rev-4F Ac-FAEKFKEHVKEYFAKFWE-NH2
(SEQ ID NO: 438)
[A-8 > H, E > D]Rev-4F Ac-FADKFKDHVKDYFAKFWD-NH2
(SEQ ID NO: 439)
[A-8 > H, E-3 > D]Rev-4F Ac-FADKFKEHVKDYFAKFWD-NH2(
(SEQ ID NO: 440)
[A-8 > H, E-7 > D]Rev-4F Ac-FAEKFKDHVKDYFAKFWD-NH2
(SEQ ID NO: 441)
[A-8 > H, D-11 > E]Rev-4F Ac-FAEKFKEHVKEYFAKFWD-NH2
(SEQ ID NO: 442)
[A-8 > H, D-18 > E]Rev-4F Ac-FAEKFKEHVKDYFAKFWE-NH2
(SEQ ID NO: 443)
[A-8 > F, F-13 > H]Rev-4F Ac-FAEKFKEFVKDYHAKFWD-NH2
(SEQ ID NO: 444)
[A-8 > F, F-13 > H, D-E switched]Rev-4F Ac-FADKFKDFVKEYHAKFWE-NH2
(SEQ ID NO: 445)
[A-8 > F, F-13 > H, E-3 > D]Rev-4F Ac-FADKFKEFVKDYHAKFWD-NH2
(SEQ ID NO: 446)
[A-8 > F, F-13 > H, E-7 > D]Rev-4F Ac-FAEKFKDFVKDYHAKFWD-NH2
(SEQ ID NO: 447)
[A-8 > F, F-13 > H, E > D]Rev-4F Ac-FADKFKDFVKDYHAKFWD-NH2
(SEQ ID NO: 448)
[A-8 > F, F-13 > H, D > E]Rev-4F Ac-FAEKFKEFVKEYHAKFWE-NH2
(SEQ ID NO: 449)
[A-8 > F, F-13 > H, D-11 > E]Rev-4F Ac-FAEKFKEFVKEYHAKFWD-NH2
(SEQ ID NO: 450)
[A-8 > F, F-13 > H, D-18 > E]Rev-4F Ac-FAEKFKEFVKDYHAKFWE-NH2
(SEQ ID NO: 451)
[A-8 > F, F16 > H]Rev-4F Ac-FAEKFKEFVKDYFAKHWD-NH2
(SEQ ID NO: 452)
[A-8 > F, F16 > H, D-E switched]Rev-4F Ac-FADKFKDFVKEYFAKHWE-NH2
(SEQ ID NO: 453)
[A-8 > F, F16 > H, D > E]Rev-4F Ac-FAEKFKEFVKEYFAKHWE-NH2
(SEQ ID NO: 454)
[A-8 > F, F16 > H, E > D]Rev-4F Ac-FADKFKDFVKDYFAKHWD-NH2
(SEQ ID NO: 455)
[A-8 > F, F16 > H, E- 3 > D]Rev-4F Ac-FADKFKEFVKDYFAKHWD-NH2
(SEQ ID NO: 456)
[A-8 > F, F16 > H, E-7 > D]Rev-4F Ac-FAEKFKDFVKDYFAKHWD-NH2
(SEQ ID NO: 457)
[A-8 > F, F16 > H, D- 11 > E]Rev-4F Ac-FAEKFKEFVKEYFAKHWD-NH2
(SEQ ID NO: 458)
[A-8 > F, F16 > H, D-18 > E]Rev-4F Ac-FAEKFKEFVKDYFAKHWE-NH2
(SEQ ID NO: 459)
Examples of class A 4F and Rev 4F analogs with beta-Nph. Similarly, alpha-Nph analogs can be designed. Similarly to the above analogs, His can be incorporated to Nph analogs. D>E analogs, E>D analogs and D−E switch analogs are additional possibilities similarly to the above described analogs.
4Nph
(SEQ ID NO: 460)
Ac-DW Nph KA Nph YDKVAEK Nph KEA Nph -NH2
[D-E switched] 4Nph
(SEQ ID NO: 461)
Ac- E W Nph KA Nph Y E KVADK Nph K D A Nph -NH2
[D > E]4Nph
(SEQ ID NO: 462)
Ac- E W Nph KA Nph Y E KVAEK Nph KEA Nph -NH2
[E > D]4Nph
(SEQ ID NO: 463)
Ac-DW Nph KA Nph YDKVA D K Nph K D A Nph -NH2
[D-1 > E]4Nph
(SEQ ID NO: 464)
Ac- E W Nph KA Nph YDKVAEK Nph KEA Nph -NH2
[D-8 > E]4Nph
(SEQ ID NO: 465)
Ac-DW Nph KA Nph Y E KVAEK Nph KEA Nph -NH2
[E-12 > D]4Nph
(SEQ ID NO: 466)
Ac-DW Nph KA Nph YDKVA D K Nph KEA Nph -NH2
[E-16 > D]4Nph
(SEQ ID NO: 467
Ac-DW Nph KA Nph YDKVAEK Nph K D A Nph -NH2
As described above for 4 Nph, a minimum of 7 additional analogs for each of the analogs given below.
[F-3, 6, > Nph]4F
(SEQ ID NO: 468)
Ac-DW Nph KA Nph YDKVAEKFKEAF-NH2
[F-14, 18 > Nph]4F
(SEQ ID NO: 469)
Ac-DWFKAFYDKVAEK Nph KEA Nph -NH2
[[F-3 > Nph]4F
(SEQ ID NO: 470)
Ac-DW Nph KAFYDKVAEKFKEAF-NH2
[F-6 > Nph]4F
(SEQ ID NO: 471)
Ac-DWFKA Nph YDKVAEKFKEAF-NH2
[F-14 > Nph]4F
(SEQ ID NO: 472)
Ac-DWFKAFYDKVAEK Nph KEAF-NH2
[F-18 > Nph]4F
(SEQ ID NO: 473)
Ac-DWFKAFYDKVAEKFKEA Nph -NH2
For each of the analog described below, a minimum of 7 additional analogs are possible as described above by switching D−E, D>E and E>D and single D or E analogs.
Rev-4Nph
(SEQ ID NO: 474)
Ac- Nph AEK Nph KEAVKDY Nph AK Nph WD-NH2
[F-3, 6 > Nph]Rev
(SEQ ID NO: 475)
Ac- Nph AEK Nph KEAVKDYFAKFWD-NH2
4F [F-13, 16]Rev-4F
(SEQ ID NO: 476)
Ac-FAEKFKEAVKDY Nph AK Nph WD-NH2
[F-3 > Nph]Rev-4F
(SEQ ID NO: 477)
Ac- Nph AEKFKEAVKDYFAKFWD-NH2
[F-6 > Nph]Rev-4F
(SEQ ID NO: 478)
Ac-FAEK Nph KEAVKDYFAKFWD-NH2
[F-13 > Nph]Rev-4F
(SEQ ID NO: 479)
Ac-FAEKFKEAVKDY Nph AKFWD-NH2
[F-16 > Nph]Rev-4F
(SEQ ID NO: 480)
Ac-FAEKEKEAVKDYFAK Nph WD-NH2
For the analogs described below, additional analogs are possible by incorporating His or alpha-Nph and beta-Nph
Rev-[D > E]-4F
(SEQ ID NO: 481)
Ac-FAEKFKEAVK E YFAKFW E -NH2
Rev-[E > D]4F
(SEQ ID NO: 482)
Ac-FA D KFK D AVKDYFAKFWD-NH2
Rev-R4-4F
(SEQ ID NO: 483)
Ac-FAE R FREAVKDYFAKFWD-NH2
Rev-R6-4F
(SEQ ID NO: 484)
Ac-FAEKF R EAVKDYFAKFWD-NH2
Rev-R10-4F
(SEQ ID NO: 485)
Ac-FAEKFKEAV R DYFAKFWD-NH2
Rev-R14-4F
(SEQ ID NO: 486)
Ac-FAEKFKEAVKDYFA R FWD-NH2
Rev-[D > E]-4F
(SEQ ID NO: 481)
Ac-FAEKFKEAVK E YFAKFW E -NH2
Rev-[E > D]4F
(SEQ ID NO: 482)
Ac-FA D KFK D AVKDYFAKFWD-NH2
Rev-R4-4F
(SEQ ID NO: 483)
Ac-FAE R FREAVKDYFAKFWD-NH2
Rev-R6-4F
(SEQ ID NO: 484)
Ac-FAEKF R EAVKDYFAKFWD-NH2
Rev-R10-4F
(SEQ ID NO: 485)
Ac-FAEKFKEAV R DYFAKFWD-NH2
Rev-R14-4F
(SEQ ID NO: 486)
Ac-FAEKFKEAVKDYFA R FWD-NH2
Rev-[D > E]-4F
(SEQ ID NO: 481)
Ac-FAEKFKEAVK E YFAKFW E -NH2
Rev-[E > D]4F
(SEQ ID NO: 482)
Ac-FA D KFK D AVKDYFAKFWD-NH2
Rev-R4-4F
(SEQ ID NO: 483)
Ac-FAE R FREAVKDYFAKFWD-NH2
Rev-R6-4F
(SEQ ID NO: 484)
Ac-FAEKF R EAVKDYFAKFWD-NH2
Rev-R10-4F
(SEQ ID NO: 485)
Ac-FAEKFKEAV R DYFAKFWD-NH2
Rev-R14-4F
(SEQ ID NO: 486)
Ac-FAEKFKEAVKDYFA R FWD-NH2
Rev-R4-4F
(SEQ ID NO: 483)
Ac-FAE R FREAVKDYFAKFWD-NH2
Rev-R6-4F
(SEQ ID NO: 487)
Ac-FAEKF R EAVKDYEAKFWD-NH2
Rev-R10-4F
(SEQ ID NO: 485)
Ac-FAEKFKEAV R DYFAKFWD-NH2
Rev-R14-4F
(SEQ ID NO: 486)
Ac-FAEKFKEAVKDYFA R FWD-NH2
Rev-[D > E]-4F
(SEQ ID NO: 481)
Ac-FAEKFKEAVK E YFAKFW E -NH2
Rev-[E > D]4F
(SEQ ID NO: 482)
Ac-FA D KFK D AVKDYFAKFWD-NH2
Rev-R4-4F
(SEQ ID NO: 483)
Ac-FAE R FREAVKDYFAKFWD-NH2
Rev-R6-4F
(SEQ ID NO: 484)
Ac-FAEKF R EAVKDYFAKFWD-NH2
Rev-R10-4F
(SEQ ID NO: 485)
Ac-FAEKFKEAV R DYFAKFWD-NH2
Rev-R14-4F
(SEQ ID NO: 486)
Ac-FAEKFKEAVKDYFA R FWD-NH2
For each of the analogs below, additional H and Nph analogs are possible using the examples described above. Each analog can yield 7 analogs with the changes described in the examples given above.
Rev3F-2
(SEQ ID NO: 488)
Ac-LFEKFAEAFKDYVAKWKD-NH2
RevR4-3F-2
(SEQ ID NO: 489)
Ac-LFE R FAEAFKDYVAKWKD-NH2
RevR10-3F2
(SEQ ID NO: 490)
Ac-LFEKFAEAF R DYVAKWKD-NH2
RevR15-3F-2
(SEQ ID NO: 491)
Ac-LFEKFAEAFKDYVA R WKD-NH2
RevR17 3F-2
(SEQ ID NO: 492)
Ac-LFEKFAEAFKDYVAKW R D-NH2
Rev[D > E]3F2
(SEQ ID NO: 493)
Ac-LFEKFAEAFK E YVAKWK E -NH2
Rev[E > D]3F-2
(SEQ ID NO: 494)
Ac-LF D KFA D AFKDYVAKWKD-NH2
Rev-[E3 > D]-3F-2
(SEQ ID NO: 495)
Ac-LF D KFAEAFKDYVAKWKD-NH2
Rev-[E7 > D]-3F-2
(SEQ ID NO: 496)
Ac-LFEKFA D AFKDYVAKWKD-NH2
Rev[D11 > E]3F-2
(SEQ ID NO: 497)
Ac-LFEKFAEAFK E YVAKWKD-NH2
Rev-[D18 > E]3F-2
(SEQ ID NO: 498)
Ac-LFEKFAEAFKDYVAKWK E -NH2
Rev3F-1
(SEQ ID NO: 499)
Ac-FAEKAWEFVKDYFAKLKD-NH2
RevR4-3F-1
(SEQ ID NO: 500)
Ac-FAE R AWEFVKDYFAKLKD-NH2
RevR10-3F-1
(SEQ ID NO: 501)
Ac-FAEKAWEFV K DYFAKLKD-NH2
RevR15-3F-1
(SEQ ID NO: 502)
Ac-FAEKAWEFVKDYFA K LKD-NH2
RevR17-3F-1
(SEQ ID NO: 503)
Ac-FAEKAWEFVKDYFAKL R D-NH2
Rev[D > E]3F-1
(SEQ ID NO: 504)
Ac-FAEKAWEFVKEYFAKLKE-NH2
Rev[E > D]3F-1
(SEQ ID NO: 505)
Ac-FADKAWDFVKDYFAKLKD-NH2
Rev[E3 > D}-3F-1
(SEQ ID NO: 506)
Ac-FADKAWEFVKDYFAKLKD-NH2
Rev[E7 > D]3F-1
(SEQ ID NO: 507)
Ac-FAEKAW D FVKDYFAKLKD-NH2
Rev-[D11 > E]3F-1
(SEQ ID NO: 508)
Ac-FAEKAWEFVK E YFAKLKD-NH2
Rev-[D18 > E]3F-1
(SEQ ID NO: 509)
Ac-FAEKAWEFVKDYFAKLK E -NH2
Rev-5F
(SEQ ID NO: 510)
Ac-FFEKFKEFVKDYFAKLWD-NH2
Rev-[D > E]5F
(SEQ ID NO: 511)
Ac-FFEKFKEFVK E YFAKLW E -NH2
Rev-[E > D]5F
(SEQ ID NO: 512)
Ac-FF D KFK D FVKDYFAKLWD-NH2
Rev-R4-5F
(SEQ ID NO: 513)
Ac-FFE R FKEFVKDYFAKLWD-NH2
Rev-R6-5F
(SEQ ID NO: 514)
Ac-FFEKF R EFVKDYFAKLWD-NH2
Rev-R10-5F
(SEQ ID NO: 515)
Ac-FFEKFKEFV R DYFAKLWD-NH2
Rev-R15-5F
(SEQ ID NO: 516)
Ac-FFEKFKEFVKDYFA R LWD-NH2
Rev-[E3 > D]-5F
(SEQ ID NO: 517)
Ac-FF D KFKEFVKDYFAKLWD-NH2
Rev-[E7 > D]5F
(SEQ ID NO: 518)
Ac-FFEKFK D FVKDYFAKLWD-NH2
Rev-[D11 > E]-5F
(SEQ ID NO: 519)
Ac-FFEKFKEFVK E YFAKLWD-NH2
Rev-[D18 > E]-5F
(SEQ ID NO: 520)
Ac-FFEKFKEFVKDYFAKLW E -NH2
Rev-5F-2
(SEQ ID NO: 521)
Ac-F L EKFKEFVKDYFAK F WD-NH2
Rev-[D > E]-5F-2
(SEQ ID NO: 522)
Ac-FLEKFKEFVK E YFAKFW E -NH2
Rev-[E > D]-5F-2
(SEQ ID NO: 523)
Ac-FL D KFK E FVKDYFAKFWD-NH2
Rev-[E3 > D]-5F-2
(SEQ ID NO: 524)
Ac-FL D KFKEFVKDYFAKFWD-NH2
Rev-[E7 > D]-5F-2
(SEQ ID NO: 525)
Ac-FLEKFK D FVKDYFAKFWD-NH2
Rev-[D11 > E]-5F-2
(SEQ ID NO: 526)
Ac-FLEKFKEFVK E YFAKFWD-NH2
Rev-[D18 > E]-5F-2
(SEQ ID NO: 527)
Ac-FLEKFKEFVKDYFAKFW E -NH2
Rev-R4-5F-2
(SEQ ID NO: 528)
Ac-FLE R FKEFVKDYFAKFWD-NH2
Rev-R6-5F-2
(SEQ ID NO: 529)
Ac-FLEKF R EFVKDYFAKFWD-NH2
RevR10-5F-2
(SEQ ID NO: 530)
Ac-FLEKFKEFV R DYFAKFWD-NH2
Rev-R16-5F-2
(SEQ ID NO: 531)
Ac-FLEKFKEFVKDYFA R FWD-NH2
Rev-6F
(SEQ ID NO: 532)
Ac-F F EKFKE FF KDYFAKLWD-NH2
Rev-[D > E]-6F
(SEQ ID NO: 533)
Ac-FFEKFKEFFK E YFAKLW E -NH2
Rev-[E > D]-6F
(SEQ ID NO: 534)
Ac-FFDKFKDFFKDYFAKLWD-NH2
Rev-R4-6F
(SEQ ID NO: 535)
Ac-FFE R FKEFFKDYFAKLWD-NH2
Rev-R6-6F
(SEQ ID NO: 536)
Ac-F F EKF R EFFKDYFAKLWD-NH2
Rev-R10-6F
(SEQ ID NO: 537)
Ac-FFEKFKEFF R DYFAKLWD-NH2
Rev-R14-6F
(SEQ ID NO: 538)
Ac-FFERFKEFFKDYFA R LWD-NH2
Rev-[E3 > D]-6F
(SEQ ID NO: 539)
Ac-FF D KFKEFFKDYFAKLWD-NH2
Rev-[E7 > D]-6F
(SEQ ID NO: 540)
Ac-FFEKEK D FFKDYFAKLWD-NH2
Rev-[D11 > E]-6F
(SEQ ID NO: 541)
Ac-FFEKFKEFFK E YFAKLWD-NH2
Rev-[D18 > E]-6F
(SEQ ID NO: 542)
Ac-FFEKFKEFFKDYFAKLW E -NH2
Rev-4F
(SEQ ID NO: 543)
Ac-FAEKFKEAVKDYFAKFWD-NH2
Rev-[D > E]-4F
(SEQ ID NO: 481)
Ac-FAEKFKEAVK E YFAKFW E -NH2
Rev-[E > D]4F
(SEQ ID NO: 482)
Ac-FA D KFK D AVKDYFAKFWD-NH2
Rev-R4-4F
(SEQ ID NO: 483)
Ac-FAE R FREAVKDYFAKFWD-NH2
Rev-R6-4F
(SEQ ID NO: 484)
Ac-FAEKF R EAVKDYFAKFWD-NH2
Rev-R10-4F
(SEQ ID NO: 485)
Ac-FAEKFKEAV R DYFAKFWD-NH2
Rev-R14-4F
(SEQ ID NO: 486)
Ac-FAEKFKEAVKDYFA R FWD-NH2
4F-2
(SEQ ID NO: 544)
Ac-DKWKAVYDKFAEAFKEFF-NH2
[D > E]-4F-2
(SEQ ID NO: 545)
Ac-EKWKAVYEKFAEAFKEFF-NH2
[E > D]-4F-2
(SEQ ID NO: 546)
Ac-DKWKAVYDKFA D AFK D FF-NH2
R2-4F-2
(SEQ ID NO: 547)
Ac-D R WKAVYDKFAEAFKEFF-NH2
R4-4F-2
(SEQ ID NO: 548)
Ac-DKW R AVYDKFAEAFKEFF-NH2
R9-4F-2
(SEQ ID NO: 549)
Ac-DKWKAVYD R FAEAFKEFF-NH2
R14-4F-2
(SEQ ID NO: 550)
Ac-DKWKAVYDKFAEAF R EFF-NH2
Rev4F-2
(SEQ ID NO: 551)
Ac-FFEKFAEAFKDYVAKWKD-NH2
Rev-[D > E]-4F-2
(SEQ ID NO: 552)
Ac-FFEKFAEAFK E YVAKWK E -NH2
Rev-[E > D]-3F-2
(SEQ ID NO: 553)
Ac-FF D KFA D AFKDYVAKWKD-NH2
Rev-R4-4F-2
(SEQ ID NO: 554)
Ac-FFE R FAEAFKDYVAKWKD-NH2
Rev-R10-4F-2
(SEQ ID NO: 555)
Ac-EFERFAEAF R DYVAKWKD-NH2
Rev-R15-4F-2
(SEQ ID NO: 556)
Ac-FFEKFAEAFKDYVA R WKD-NH2
Rev-R17-4F-2
(SEQ ID NO: 557)
Ac-FFE R FAEAFKDYVAKW R D-NH2
Rev-[E3 > D]-4F-2
(SEQ ID NO: 558)
Ac-FF D KFAEAFKDYVAKWKD-NH2
Rev-[E7 > D]-4F-2
(SEQ ID NO: 559)
Ac-FFEKFA D AFKDYVAKWKD-NH2
Rev-[D11 > E]-4F-2
(SEQ ID NO: 560)
Ac-FFERFAEAFK E YVAKWKD-NH2
Rev- [D18 > E]-4F-2
(SEQ ID NO: 561)
Ac-FFERFAEAFKDYVAKWKE-NH2
Rev-7F
(SEQ ID NO: 562)
Ac-FFEKFKEFFKDYFAKFWD-NH2
Rev-[E > D]-7F
(SEQ ID NO: 563)
Ac-FF D KFK D FFKDYFAKFWD-NH2
Rev-[D > E]-7F
(SEQ ID NO: 564)
Ac-FFEKFKEFFK E YFAKFW E -NH2
Rev-R4-7F
(SEQ ID NO: 565)
Ac-FFE R FKEFFKDYFAKFWD-NH2
Rev-R6-7F
(SEQ ID NO: 566)
Ac-FFEKF R EFFKDYFAKFWD-NH2
Rev-R10-7F
(SEQ ID NO: 567)
Ac-FFEKFKEFF R DYFAKFWD-NH2
Rev-R14-7F
(SEQ ID NO: 568)
Ac-FFEKFKEFFKDYFA R FWD-NH2
Rev-[E3 > D]-7F
(SEQ ID NO: 569)
Ac-FF D KFKEFFKDYFAKFWD-NH2
Rev-[E7 > D]7F
(SEQ ID NO: 570)
Ac-FFEKFK D FFKDYFAKFWD-NH2
Rev-[D11 > E]-7F
(SEQ ID NO: 571)
Ac-FFEKFKEFFK E YFAKFWD-NH2
Rev-[D18 > E]-7F
(SEQ ID NO: 572)
Ac-FFEKFKEFFKDYFAKFW E -NH2
It is also noted that any of the peptides described herein can comprise non-natural amino acids in addition to or instead of the corresponding the natural amino acids identified herein. Such modifications include, but are not limited to acetylation, amidation, formylation, methylation, sulfation, and the like. Illustrative non-natural amino acids include, but are not limited to Ornithine, norleucine, norvaline, N-methylvaline, 6-N-methyllysine, N-methylisoleucine, N-methylglycine, sarcosine, inosine, allo-isoleucine, isodesmolysine, 4-hydroxyproline, 3-hydroxyproline, allo-hydroxylysine, hydoxylisine, N-ethylasparagine, N-ethylglycine, 2,3-diaminopropionic acid, 2,2′-diaminopropionic acid, desmosine, 2,4-diaminobutyric acid, 2-aminopimelic acid, 3-aminoisobutyric acid, 2-aminoisobutyric acid, 2-aminoheptanoic acid, 6-aminocaproic acid, 4-aminobutyric acid, 2-aminobutyric acid, beta-alanine, 3-aminoadipic acid, 2-aminoadipic acid, and the like. In certain embodiments and one or more of the “natural” amino acids of the peptides described herein, can be substituted with the corresponding non-natural amino acid (e.g. as describe above).
In certain embodiments, this invention contemplates particularly the use of modified lysines. Such modifications include, but are not limited to, biotin modification of epsilon lysines and/or methylation of the epsilon lysines. Illustrative peptide comprising epsilon methylated lysines include, but are not limited to: Ac-D-W-F-K(eCH3)2-A-F-Y-D-K(eCH3)2-V-A-E-K(eCH3)-2-F-K(eCH3)2-E-A-F-NH(CH3)2 (SEQ ID NO:573) and: Ac-DWFK(eCH3)2AFYDK(eCH3)2VAEK(eCH3)2FK(eCH3)2EAF-NH(CH3) (SEQ ID NO:574). Other modified amino acids include but are not limited to ornithine analogs and homoaminoalanine analogs (instead of (CH2)4—NH2 for Lys it can be —(CH2)2—NH2 for Haa and —(CH2)3—NH2 for Orn] and the like. It is noted that these modifications are illustrative and not intended to be limiting. Illustrative 4F analogues that possess modified amino acids are shown in Table 6.
TABLE 6
Illustrative 4F analogs that comprise modified amino acids.
εN-Dimethyl-Lys derivative of 4F (εN-Dime)
Ac-D-W-F-K(εN-Dime)-A-F-Y-D-K(εN-Dime)-V-A-E-K(εN-Dime)-F-
K(εN-Dime)-E-A-F-NH2 (SEQ ID NO: 575)
Ac-D-W-F-K-(εN-Dime)-A-F-Y-D-K(εN-Dime)-V-A-E-K(εN-Dime)-F-
K((εN- Dime)-E-A-F-NH-Me (SEQ ID NO: 576)
Ac-D-W-F-K-(εN-Dime)-A-F-Y-D-K(εN-Dime)-V-A-E-K(εN-Dime)-F-
K(εN- Dime)-E-A-F-N-(Me)2 (SEQ ID NO: 577)
εN-Diethyl-Lys derivatives of 4F (εN-Diet)
Ac-D-W-F-K(εN-Diet)-A-F-Y-D-K(εN-Diet)-V-A-E-K(εN-Diet)-F-K(εN-
Diet)- E-A-F-NH2 (SEQ ID NO: 578)
Ac-D-W-F-K(εN -Diet)-A-F-Y-D-K(εN -Diet)-V-A-E-K(εN -Diet)-F-K(εN -
Diet)- E-A-F-NH-Et (SEQ ID NO: 579)
Ac-D-W-F-K(εN -Diet)-A-F-Y-D-K(εN -Diet)-V-A-E-K(εN -Diet)-F-K(εN -
Diet)- E-A-F-NH-(Et)2 (SEQ ID NO: 580)
εN-Monomethyl-Lys derivative of 4F (εN -Me)
Ac-D-W-F-K(EN Me)-A-F-Y-D-K(εN -Me)-V-A-E-K(εN -Me)-F-K(εN-
Me)- E-A-F-NH2 (SEQ ID NO: 581)
Ac-D-W-F-K(εN -Me)-A-F-Y-D-K(εN -Me)-V-A-E-K(εN -Me)-F-K(εN-
Me)- E-A-F-NH-Me (SEQ ID NO: 582)
Ac-D-W-F-K(εN -Me)-A-F-Y-D-K(εN -Me)-V-A-E-K(εN -Me)-F-K(εN-
Me)- E-A-F-N-(Me)2 (SEQ ID NO: 583)
εN-ethylLys derivative of 4F (εN -Et)
Ac-D-W-F-K(εN -Et)-A-F-Y-D-K(εN -E0-V-A-E-K(εN -Et)-F-K(εN -
Et)-E- A-F-NH2 (SEQ ID NO: 584)
Ac-D-W-F-K(εN -Et)-A-F-Y-D-K(εN -E0-V-A-E-K(εN -Et)-F-K(εN -
E0-E- A-F-NH-Et (SEQ ID NO: 585)
Ac-D-W-F-K(εN -Et)-A-F-Y-D-K(εN -Et)-V-A-E-K(εN -Et)-F-K(εN -
Et)-E- A-F-NH-(Et)2 (SEQ ID NO: 586)
HomoLys analogs of 4F (hK) (--CH2)5-NH2
Ac-D-W-F-hK-A-F-Y-D-hK-V-A-E-hK-F-hK-E-A-F-NH2 (SEQ ID NO: 587)
Ac-D-W-F-hK(εN-Dime)-A-F-Y-D-hK(εN -Dime)-V-A-E-hK(εN -Dime)-F-
hK(εN -Dime)-E-A-F-NH2 (SEQ ID NO: 588)
Ac-D-W-F-hK(εN -Dime)-A-F-Y-DhK(εN -Dime)-V-A-E-hK(εN -Dime)-F-
hK(εN -Dime)-E-A-F-N-(Me)2 (SEQ ID NO: 589)
Ac-D-W-F-hK(εN -Dime)-A -F -Y - D - hK(εN -Dime)-V-A-E-hK(εN -
Dime)-F- hK(εN -Dime)-E-A-F-NH-Me (SEQ ID NO: 590)
Ac-D-W-F-hK(εN -Diet)-AF-Y-D-hK(εN -Diet)-V-A-E-hK(εN -Diet)-F-
hK(εN -Diet)-E-A-F-NH-Et (SEQ ID NO: 591)
Ac-D-W-F-hK(εN -Me)-A-F-Y-D-hK(εN -Me)-V-A-E-hK(εN -Me)-F-
hK(εN -Me)-E-A-F-NH2 (SEQ ID NO: 592)
Ac-D-W-F-hK(εN -Me)-A-F-Y-D-hK(εN -Me)-V-A-E-hK(εN -Me)-F-
hK(εN -Me)-E-A-F-NH-Me (SEQ ID NO: 593)
Ac-D-W-F-hK(εN -Me)-A-F-Y-D-hK(εN -Me)-V-A-E-hK(εN -Me)-F-
hK(εN -Me)-E-A-F-N-(Me)2 (SEQ ID NO: 594)
Ac-D-W-F-hK(εN -Et)-A-F-D-hK(εN -Et)-V-A-E-hK(εN -Et)-F-
hK(εN -Et)-E-A-F-NH2 (SEQ ID NO: 595)
Ac-D-W-F-hK(εN-Et-A-F-Y-D-hK(εN -Et)-V-A-E-hK(εN -Et)-F-
hK(εN -Et)-E-A-F-NH-Et (SEQ ID NO: 596)
Ac-D-W-F-hK(εN -Et)-A-F-Y-D-hK(εN -Et)-V-A-E-hK(εN -Et)-F-
hK(εN -Et)-E-A-F-NH-(Et)2 (SEQ ID NO: 597)
4F analogs in which K is replaced O (O = Ornithine, --(CH2)3-NH2)
Ac-D-W-F-O-A-F-Y-D-O-V-A-E-O-F-O-E-A-F-NH2(SEQ ID NO: 598)
Ac-D-W-F-O(δN-Dime)-A-F-Y-D-O(δN-Dime)-V-A-E-O(δN -Dime)-F-O(δN -
Dime)-E-A-F-NH2 (SEQ ID NO: 599)
Ac-D-W-F-O(δN -Dime)-A-F-Y-D-O(δN-Dime)-V-A-E-O(δN -Dime)-F-O(δN-
Dime)-E-A-F-N-(Me)2 (SEQ ID NO: 600)
Ac-D-W-F-O(δN -Dime)-A-F-Y-D-O(δN -Dime)-V-A-E-O(δN -Dime)-F-O(δN - Dime)-
E-A-F-NH-Me (SEQ ID NO: 601)
Ac-D-W-F-O(δN -Diet)-A-F-Y-D-O(δN -Diet)-V-A-E-O(δN -Diet)-F-O(δN - Diet)-E-
A-F-NH-Et (SEQ ID NO: 602)
Ac-D-W-F-O(δN-Me)-A-F-Y-D-O(δN-Me)-V-A-E-O(δN-Me)-F-O(δN-
Me)- E-A-F-NH2 (SEQ ID NO: 603)
Ac-D-W-F-O(δN-Me)-A-F-Y-D-O(δN-Me)-V-A-E-O(δN-Me)-F-O(δN-
Me)- E-A-F-NH-Me (SEQ ID NO: 604)
Ac-D-W-F-O(δN-Me)-A-F-Y-D-O(δN-Me)-V-A-E-O(δN-Me)-F-O(δN-
Me)- E-A-F-N-(Me)2 (SEQ ID NO: 605)
Ac-D-W-F-O(δN -Et)-A-F-Y-D-O(δN -Et)-V-A-E-O(δN -Et)-F-O(δN -
Et)-E- A-F-NH2 (SEQ ID NO: 606)
Ac-D-W-F-O(δN -Et)-A-F-Y-D-O(δN -Et)-V-A-E-O(δN -Et)-F-O(δN -
Et)-E- A-F-NH-Et (SEQ ID NO: 607)
Ac-D-W-F-O(δN -Et)-A-F-Y-D-O(δN-Et)-V-A-E-OdεN-Et)-F-O(δN-Et)-E-
A-F-NH-(Et)2 (SEQ ID NO: 608)
4. Dual Domain Peptides
Dual domain peptides are also disclosed. Dual domain peptides can be synthetic Apo E-mimicking peptides, consisting of a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide.
Also disclosed are synthetic Apo E-mimicking peptides, consisting of a combination of the disclosed receptor binding domains of apolipoprotein B and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide. Non-limiting examples of the disclosed synthetic Apo E-mimicking peptides are provided in Table 7. The disclosed synthetic Apo E-mimicking peptides can also be N-terminally protected using acetyl and amino groups. Table 7 provides non-limiting representative examples of the disclosed synthetic Apo E-mimicking peptides comprising a dual domain.
TABLE 7
Dual domain peptides.
Non-limiting Examples of the Disclosed
Synthetic Apo E mimetics
Receptor Binding
Domains of Apo E Lipid-Associating Peptides
LRKLRKRLLR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 4) (SEQ ID NO: 5)
LRKLRKRLLR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 4) (SEQ ID NO: 5)
LRKLRKRLLR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 4) (SEQ ID NO: 5)
LRKMRKRLMR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 7) (SEQ ID NO: 5)
LRKMRKRLMR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 7) (SEQ ID NO: 5)
LRKLPKRLLR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 8) (SEQ ID NO: 5)
LRNVRKRLVR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 9) (SEQ ID NO: 5)
MRKLRKRVLR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 10) (SEQ ID NO: 5)
LRRLRRRLLR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 11) (SEQ ID NO: 5)
LRKLRKRFFFFR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 12) (SEQ ID NO: 5)
LRKLRKRLLR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 4) (SEQ ID NO: 16)
LRKLRKRLLR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 4) (SEQ ID NO: 16)
LRKLRKRLLR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 4) (SEQ ID NO: 16)
LRKMRKRLMR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 7) (SEQ ID NO: 16)
LRKMRKRLMR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 7) (SEQ ID NO: 16)
LRKLPKRLLR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 8) (SEQ ID NO: 16)
LRNVRKRLVR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 9) (SEQ ID NO: 16)
MRKLRKRVLR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 10) (SEQ ID NO: 16)
LRRLRRRLLR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 11) (SEQ ID NO: 16)
LRKLRKRFFFFR DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 12) (SEQ ID NO: 16)

i. Domain Switched Peptides
Also disclosed are synthetic Apo E mimetics, consisting of a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a domain switched orientation. Also disclosed are synthetic Apo E mimetics, consisting of a combination of the disclosed receptor binding domains of apolipoprotein B and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a domain switched orientation. These peptides can be referred to as “domain switched” “switched domain”, or “switched” peptides. For example, disclosed are synthetic Apo E mimetics, consisting of a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a domain switched orientation to those described above and in Table 7. Specifically, the lipid-associating peptide is covalently linked to the receptor binding domain of apolipoprotein E such that the lipid-associating peptide is at the N-terminus of the synthetic apolipoprotein E-mimicking peptide. Table 8 provides non-limiting examples of the disclosed synthetic Apo E mimetics comprising a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a domain switched orientation.
TABLE 8
Domain Switched Peptides.
Non-limiting Examples of Disclosed
Synthetic Apo E mimetics
Lipid-Associating Receptor Binding Domains
Peptides of ApoE
DWLKAFYDKVAEKLKEAF LRKLRKRLLR (SEQ ID NO: 6)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF LRKLRKRLLR (SEQ ID NO: 6)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF LRKLRKRLLR (SEQ ID NO: 6)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF LRKMRKRLMR (SEQ ID NO: 7)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF LRKMRKRLMR (SEQ ID NO: 7)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF LRKLPKRLLR (SEQ ID NO: 8)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF LRNVRKRLVR (SEQ ID NO: 9)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF MRKLRKRVLR (SEQ ID NO: 10)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF LRRLRRRLLR (SEQ ID NO: 11)
(SEQ ID NO: 5)
DWLKAFYDKVAEKLKEAF LRKLRKRFFFFR (SEQ ID NO: 12)
(SEQ ID NO: 5)
DWFKAFYDKVAEKFKEAF LRKLRKRLLR (SEQ ID NO: 6)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF LRKLRKRLLR (SEQ ID NO: 6)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF LRKLRKRLLR (SEQ ID NO: 6)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF LRKMRKRLMR (SEQ ID NO: 7)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF LRKMRKRLMR (SEQ ID NO: 7)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF LRKLPKRLLR (SEQ ID NO: 8)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF LRNVRKRLVR (SEQ ID NO: 9)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF MRKLRKRVLR (SEQ ID NO: 10)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF LRRLRRRLLR (SEQ ID NO: 11)
(SEQ ID NO: 16)
DWFKAFYDKVAEKFKEAF LRKLRKRFFFFR (SEQ ID NO: 12)
(SEQ ID NO: 16)
The disclosed domain switched synthetic Apo E mimetics can also be N-terminally protected using acetyl and amino groups.
ii. Peptides with Reverse Orientation
Also disclosed are synthetic Apo E-mimicking peptides, consisting of a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a reversed orientation. For example, disclosed are synthetic Apo E-mimicking peptides, consisting of a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein either the sequence of the receptor binding domain or the sequence of the lipid-associating peptide or both sequences are in the reversed orientation. Also disclosed are synthetic Apo E-mimicking peptides, consisting of a combination of the disclosed receptor binding domains of apolipoprotein B and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a reversed orientation. Table 9 provides non-limiting examples of the disclosed synthetic Apo E-mimicking peptides comprising a combination of the disclosed receptor binding domains of apolipoprotein E and the disclosed lipid-associating peptides, wherein said receptor binding domain is covalently linked to said lipid-associating peptide in a reversed orientation.
TABLE 9
Reverse Orientation Peptides.
Non-limiting Examples of Synthetic
Apo E mimetics
Receptor Binding
Domains of Apo E Lipid-Associating Peptides
RLLRKRLKRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 609) (SEQ ID NO: 5)
RLLRKRLKRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 609) (SEQ ID NO: 5)
RLLRKRLKRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 609) (SEQ ID NO: 5)
RMLRKRMKRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 610) (SEQ ID NO: 5)
RMLRKRMKRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 610) (SEQ ID NO: 5)
RLLRKPLKRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 611) (SEQ ID NO: 5)
RVLRKRVNRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 612) (SEQ ID NO: 5)
RLVRKRLKRM DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 613) (SEQ ID NO: 5)
RLLRRRLRRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 614) (SEQ ID NO: 5)
RFFRKRLKRL DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 615) (SEQ ID NO: 5)
RLLRKRLKRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 609) (SEQ ID NO: 16)
RLLRKRLKRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 609) (SEQ ID NO: 16)
RLLRKRLKRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 609) (SEQ ID NO: 16)
RMLRKRMKRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 610) (SEQ ID NO: 16)
RMLRKRMKRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 610) (SEQ ID NO: 16)
RLLRKPLKRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 611) (SEQ ID NO: 16)
RVLRKRVNRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 612) (SEQ ID NO: 16)
RLVRKRLKRM DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 613) (SEQ ID NO: 16)
RLLRRRLRRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 614) (SEQ ID NO: 16)
RFFRKRLKRL DWFKAFYDKVAEKFKEAF
(SEQ ID NO: 615) (SEQ ID NO: 16)
LRKLRKRLLR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 4) (SEQ ID NO: 616)
LRKLRKRLLR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 4) (SEQ ID NO: 616)
LRKLRKRLLR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 4) (SEQ ID NO: 616)
LRKMRKRLMR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 7) (SEQ ID NO: 616)
LRKMRKRLMR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 7) (SEQ ID NO: 616)
LRKLPKRLLR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 4) (SEQ ID NO: 616)
LRNVRKRLVR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 9) (SEQ ID NO: 616)
MRKLRKRVLR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 10) (SEQ ID NO: 616)
LRRLRRRLLR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 6) (SEQ ID NO: 616)
LRKLRKRFFR FAEKLKEAVKDYFAKLWD
(SEQ ID NO: 12) (SEQ ID NO: 616)
LRKLRKRLLR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 4) (SEQ ID NO: 617)
LRKLRKRLLR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 4) (SEQ ID NO: 617)
LRKLRKRLLR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 4) (SEQ ID NO: 617)
LRKMRKRLMR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 7) (SEQ ID NO: 617)
LRKMRKRLMR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 7) (SEQ ID NO: 617)
LRKLPKRLLR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 8) (SEQ ID NO: 617)
LRNVRKRLVR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 9) (SEQ ID NO: 617)
MRKLRKRVLR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 10) (SEQ ID NO: 617)
LRRLRRRLLR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 4) (SEQ ID NO: 617)
LRKLRKRFFR FAEKFKEAVKDYFAKFWD
(SEQ ID NO: 12) (SEQ ID NO: 617)
iii. Scrambled Peptides
Also disclosed are synthetic Apo E-mimicking peptides, consisting of: a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein said receptor binding domain is covalently linked to said lipid-associating peptide, wherein the receptor binding domain of apolipoprotein E is scrambled. For example, disclosed is a synthetic apolipoprotein E-mimicking peptide, consisting of: a receptor binding domain of apolipoprotein E comprising the amino acid sequence of D-W-L-K-A-F-V-Y-D-K-V-F-K-L-K-E-F-F (SEQ ID NO:69); and a lipid-associating peptide, wherein said receptor binding domain is covalently linked to said lipid-associating peptide. Also disclosed are synthetic Apo E-mimicking peptides, consisting of: a receptor binding domain of apolipoprotein B and a lipid-associating peptide, wherein said receptor binding domain is covalently linked to said lipid-associating peptide, wherein the receptor binding domain of apolipoprotein B is scrambled.
Also disclosed are synthetic Apo E-mimicking peptides, consisting of: a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein said receptor binding domain is covalently linked to said lipid-associating peptide, wherein the lipid-associating peptide is scrambled. For example, disclosed herein is a synthetic Apo E-mimicking peptides, comprising: a lipid binding domain of apolipoprotein E comprising the amino acid sequence of E-W-L-K-A-F-V-Y-E-K-V-F-K-L-K-E-F-F (SEQ ID NO:70) and a receptor binding domain peptide, wherein said lipid binding domain is covalently linked to said receptor binding domain peptide.
Also disclosed are synthetic Apo E mimetics, consisting of: a receptor binding domain of apolipoprotein E and a lipid-associating peptide of apolipoprotein E, wherein receptor binding domain is covalently linked to said lipid-associating peptide, wherein both the receptor binding domain and the lipid-associating peptide are scrambled. Table 10 provides non-limiting examples of the disclosed scrambled synthetic Apo E mimetics comprising a receptor binding domain of apolipoprotein E and a lipid-associating peptide, wherein said receptor binding domain is covalently linked to said lipid-associating peptide, wherein the receptor binding domain of apolipoprotein E is scrambled.
TABLE 10
Scrambled Domain Peptides.
Receptor  Lipid-
Binding Domains Associating
Name of Apo E Peptides
hE-Sc18A LRKLRKRLLR KAFEEVLAKKFYDKALWD
(hE with (SEQ ID NO: 4) (SEQ ID NO: 660)
Sc18A also
referred
toas Sc2F)
SchE-18A LRLLRKLKRR DWLKAFYDKVAEKLKEAF
(SEQ ID NO: 661) (SEQ ID NO: 5)
The disclosed scrambled synthetic Apo E mimetics can also be N-terminally and C-terminally protected using acetyl and amide groups. The disclosed scrambled synthetic Apo E mimetics can also be reverse-oriented as described above.
iv. Linkages
Any suitable linker can be used in accordance with the present invention. The peptide linkages can be selected from the group consisting of: —CH2NH—, —CH2S—, —CH2—CH2—, —CH═CH—(cis and trans), —COCH2—, —CH(OH)CH2—, —CH2SO—, etc. by methods known in the art and further described in the following references: Spatola (1983) p. 267 in Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins, B. Weinstein, eds., Marcel Dekker, New York; Spatola (1983) Vega Data 1(3) Peptide Backbone Modifications. (general review); Morley (1980) Trends Pharm Sci pp. 463-468 (general review); Hudson et al. (1979) Int J PeptProt Res 14:177-185 (—CH2NH—, CH2CH2—); Spatola et al. (1986) Life Sci 38:1243-1249 (—CH2—S); Hann, (1982) J ChemSoc Perkin Trans I 307-314 (—CH—CH—, cis and trans); Almquist et al. (1980) J Med. Chem. 23:1392-1398 (—COCH2—); Jennings-White et al. (1982) Tetrahedron Lett. 23:2533 (—COCH2—); Szelke et al., European Appln. EP 45665 (1982) CA: 97:39405 (1982) (—CH(OH)CH2-); Holladay et al. (1983) Tetrahedron Lett 24:4401-4404 (—C(OH)CH2—); and Hruby (1982) Life Sci., 31:189-199 (—CH2—S—)).
One particularly preferred non-peptide linkage is —CH2NH—. Such peptide mimetics may have significant advantages over polypeptide embodiments, including, for example: more economical production, greater chemical stability, enhanced pharmacological properties (half-life, absorption, potency, efficacy, etc.), reduced antigenicity, and others.
In one aspect, the linker is a cleavable linker. To give but a few examples, cleavable linkers include protease cleavable peptide linkers, nuclease sensitive nucleic acid linkers, lipase sensitive lipid linkers, glycosidase sensitive carbohydrate linkers, pH sensitive linkers, hypoxia sensitive linkers, photo-cleavable linkers, heat-labile linkers, enzyme cleavable linkers (e.g., esterase cleavable linker), ultrasound-sensitive linkers, x-ray cleavable linkers, etc.
5. Variants
The receptor binding domain or the lipid-associating peptide can be modified or altered as described above. For example, the receptor binding domain or the lipid-associating peptide can be mutated, scrambled, and/or reverse-oriented. Any other modifications or alterations disclosed herein for the dual-domain polypeptides can also be used for the single-domain peptides.
Numerous other variants or derivatives of the peptides disclosed herein are also contemplated. For example, scrambled peptides can also be reverse-oriented, or can be in a switched orientation. Additionally, reverse-oriented peptides can be in a switched orientation. All other combinations of the disclosed peptides are also contemplated. Non-limiting examples of the peptides have been described herein (see Tables 1-5, for example). As used herein, the term “analog” is used interchangeably with “variant” and “derivative.” Variants and derivatives are well understood to those of skill in the art and can involve amino acid sequence modifications. Such, amino acid sequence modifications typically fall into one or more of three classes: substantial; insertional; or deletional variants. Insertions include amino and/or carboxyl terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions ordinarily are smaller insertions than those of amino or carboxyl terminal fusions, for example, on the order of one to four residues. These variants ordinarily are prepared by site-specific mutagenesis of nucleotides in the DNA encoding the protein, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, for example M13 primer mutagenesis and PCR mutagenesis. Amino acid substitutions are typically of single residues, but can occur at a number of different locations at once. Substitutions, deletions, insertions or any combination thereof may be combined to arrive at a final derivative or analog. Substitutional variants are those in which at least one residue has been removed and a different residue inserted in its place. Such substitutions generally are made in accordance with Tables 11 and 12 and are referred to as conservative substitutions.
Substantial changes in function or immunological identity are made by selecting substitutions that are less conservative than those in Table 11, i.e., selecting residues that differ more significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. The substitutions which in general are expected to produce the greatest changes in the protein properties are those in which: (a) the hydrophilic residue, e.g. seryl or threonyl, is substituted for (or by) a hydrophobic residue, e.g., leucyl, isoleucyl, phenylalanyl, valyl or alanyl; Tryptophan, Tyrosinyl (b) a cysteine or proline is substituted for (or by) any other residue; (c) a residue having an electropositive side chain, e.g., lysyl, arginyl, or hystidyl, is substituted for (or by) an electronegative residue, e.g. glutamyl or aspartyl; or (d) a residue having a bulky side chain, e.g., phenylalanine, is substituted for (or by) one not having a side chain, e.g., glycine, in this case, or (e) by increasing the number of sites for sulfation and/or glycosylation.
TABLE 11
Amino Acid Substitutions
Non-limiting
Exemplary
Original Conservative
Residue Substitutions
Ala Ser
Arg Gly; Gln; Lys
Asn Gln; His
Asp Glu
Cys Ser
Gln Asn; Lys
Glu Asp
Gly Ala
His Asn; Gln
Ile Leu; Val
Leu Ile; Val
Lys Arg; Gln
Met Leu; Ile
Phe Met; Leu; Tyr
Ser Thr
Thr Ser
Trp Tyr
Tyr Trp; Phe
Val Ile; Leu
TABLE 12
Amino Acid Abbreviations
Amino Acid Abbreviations
Alanine Ala (A)
Allosoleucine AIle
Arginine Arg (R)
Asparagine Asn (N)
Aspartic Acid Asp (D)
Cysteine Cys (C)
Glutamic Acid Glu (E)
Glutamine Gln (Q)
Glycine Gly (G)
Histidine His (H)
Isolelucine Ile (I)
Leucine Leu (L)
Lysine Lys (K)
Phenylalanine Phe (F)
Praline Pro (P)
Pyroglutamic Acid PGlu (U)
Serine Ser (S)
Threonine Thr (T)
Tyrosine Tyr (Y)
Tryptophan Trp (W)
Valine Val (V)
It is understood that one way to define the variants and derivatives of the disclosed proteins herein is to define them in terms of homology/identity to specific known sequences. Specifically disclosed are variants of synthetic Apo E mimetics and other proteins or peptides herein disclosed which have at least, 70% or at least 75% or at least 80% or at least 85% or at least 90% or at least 95% homology to the synthetic Apo E mimetics specifically recited herein. Those of skill in the art readily understand how to determine the homology of two proteins.
The polypeptides can be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art. Modifications can occur anywhere in the polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. The same type of modification can be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide can have many types of modifications. Modifications include, without limitation, acetylation, acylation, ADP-ribosylation, amidation, covalent cross-linking or cyclization, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of a phosphytidylinositol, disulfide bond formation, demethylation, formation of cysteine or pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristolyation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, and transfer-RNA mediated addition of amino acids to protein such as arginylation. (See Proteins—Structure and Molecular Properties 2nd Ed., T. E. Creighton, W.H. Freeman and Company, New York (1993); Posttranslational Covalent Modification of Proteins, B. C. Johnson, Ed., Academic Press, New York, pp. 1-12 (1983)).
Variants can also include peptidomimetics. As used herein, “peptidomimetic” means a mimetic of a function of a protein which includes some alteration of the normal peptide chemistry. Peptidomimetics typically are short sequences of amino acids that in biological properties mimic one or more function(s) of a particular protein. Peptide analogs enhance some property of the original peptide, such as increases stability, increased efficacy, enhanced delivery, increased half-life, etc. Methods of making peptidomimetics based upon a known polypeptide sequence is described, for example, in U.S. Pat. Nos. 5,631,280; 5,612,895; and 5,579,250. Use of peptidomimetics can involve the incorporation of a non-amino acid residue with non-amide linkages at a given position. One embodiment of the present invention is a peptidomimetic wherein the compound has a bond, a peptide backbone or an amino acid component replaced with a suitable mimic Some non-limiting examples of unnatural amino acids which may be suitable amino acid mimics include β-alanine, L-α-amino butyric acid, L-γ-amino butyric acid, L-α-amino isobutyric acid, L-ϵ-amino caproic acid, 7-amino heptanoic acid, L-aspartic acid, L-glutamic acid, N-ϵ-Boc-N-α-CBZ-L-lysine, N-ϵ-Boc-N-α-Fmoc-L-lysine, L-methionine sulfone, L-norleucine, L-norvaline, N-α-Boc-N-δCBZ-L-omithine, N-δ-Boc-N-α-CBZ-L-ornithine, Boc-p-nitro-L-phenylalanine, Boc-hydroxyproline, and Boc-L-thioproline.
6. Nucleic Acids
As this specification discusses various peptide sequences it is understood that the nucleic acids that can encode those polypeptide sequences are also disclosed. This would include all degenerate sequences related to a specific polypeptide sequence, i.e. all nucleic acids having a sequence that encodes one particular polypeptide sequence as well as all nucleic acids, including degenerate nucleic acids, encoding the disclosed variants and derivatives of the protein sequences. Thus, while each particular nucleic acid sequence may not be written out herein, it is understood that each and every sequence is in fact disclosed and described herein through the disclosed polypeptide sequences.
7. Blocking/Protecting Groups and D Residues
The disclosed compositions can comprise an acetyl group followed by a protecting group. The protecting group can be, but is not limited to, a fatty acid. The fatty acids can be saturated, unsaturated or essential fatty acids. Fatty acids can include but are not limited to DHA, EPA, linoleic acid, or any other saturated amino acid such as myristic acid.
While the various compositions described herein may be shown with no protecting groups, in certain embodiments (e.g., particularly for oral administration), they can bear one, two, three, four, or more protecting groups. The protecting groups can be coupled to the C- and/or N-terminus of the peptide(s) and/or to one or more internal residues comprising the peptide(s) (e.g., one or more R-groups on the constituent amino acids can be blocked). Thus, for example, in certain embodiments, any of the peptides described herein can bear, e.g., an acetyl group protecting the amino terminus and/or an amide group protecting the carboxyl terminus. One example of such a “dual protected peptide” is Ac-LRKLRKRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO:1) with blocking groups), either or both of these protecting groups can be eliminated and/or substituted with another protecting group as described herein. Without being bound by a particular theory, it was a discovery of this invention that blockage, particularly of the amino and/or carboxyl termini of the subject peptides of this invention can improve oral delivery and can also increase serum half-life.
A wide number of protecting groups are suitable for this purpose. Such groups include, but are not limited to acetyl, amide, and alkyl groups with acetyl and alkyl groups being particularly preferred for N-terminal protection and amide groups being preferred for carboxyl terminal protection. For example, the protecting groups can include, but are not limited to alkyl chains as in fatty acids, propeonyl, formyl, and others. Carboxyl protecting groups include amides, esters, and ether-forming protecting groups can also be used. For example, an acetyl group can be used to protect the amino terminus and an amide group can be used to protect the carboxyl terminus. These blocking groups enhance the helix-forming tendencies of the peptides. Additional blocking groups include alkyl groups of various lengths, e.g., groups having the formula: CH3(CH2)nCO where n ranges from about 1 to about 20, preferably from about 1 to about 16 or 18, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.
Additionally, the protecting groups include, but are not limited to alkyl chains as in fatty acids, propeonyl, formyl, and others. For example, carboxyl protecting groups can include amides, esters, and ether-forming protecting groups. These blocking groups can enhance the helix-forming tendencies of the peptides. Blocking groups can include alkyl groups of various lengths, e.g., groups having the formula: CH3(CH2)nCO where n ranges from about 3 to about 20, preferably from about 3 to about 16, more preferably from about 3 to about 13, and most preferably from about 3 to about 10.
Other protecting groups include, but are not limited to Fmoc, t-butoxycarbonyl (t-BOC), 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-florenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, Xanthyl (Xan), Trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), Benzyloxy (BzlO), Benzyl (Bzl), Benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys), 1-(4,4-dimentyl-2,6-diaxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl—Z), 2-bromobenzyloxy-carbonyl (2-Br—Z), Benzyloxymethyl (Bom), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), Acetyl (Ac), and Trifluoroacetyl (TFA).
Protecting/blocking groups are well known to those of skill as are methods of coupling such groups to the appropriate residue(s) comprising the peptides of this invention (see, e.g., Greene et al., (1991) Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc. Somerset, N.J.). For example, acetylation can be accomplished during the synthesis when the peptide is on the resin using acetic anhydride. Amide protection can be achieved by the selection of a proper resin for the synthesis.
The compositions disclosed herein can also comprise one or more D-form (dextro rather than levo) amino acids as described herein. For example, at least two enantiomeric amino acids, at least 4 enantiomeric amino acids or at least 8 or 10 enantiomeric amino acids can be in the “D” form amino acids. Additionally, every other, or even every amino acid (e.g., every enantiomeric amino acid) of the peptides described herein is a D-form amino acid.
Additionally, at least 50% of the enantiomeric amino acids can be “D” form, at least 80% of the enantiomeric amino acids are “D” form, at least 90%, or even all of the enantiomeric amino acids can be in the “D” form amino acids.
FMOC-Aha can be added to the growing chain as the last amino acid using the normal amino acid chain extension procedure (use of HOBt+DCC or HBTU as condensing agents). After the removal of the FMOC group using 20% piperidine in DMF, the NH2 can be acetylated using either excess of acetic anhydride under basic conditions or by condensing acetic acid using amino acid condensing agents used for peptide chain elongation.
C. Pharmaceutical Compositions
Disclosed are pharmaceutical compositions comprising any of the synthetic ApoE-mimicking peptides disclosed herein and a pharmaceutically acceptable carrier.
By “pharmaceutically acceptable” is meant a material or carrier that would be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art. Examples of carriers include dimyristoylphosphatidyl (DMPC), phosphate buffered saline or a multivesicular liposome. For example, PG:PC:Cholesterol:peptide or PC:peptide can be used as carriers in this invention. Other suitable pharmaceutically acceptable carriers and their formulations are described in Remington: The Science and Practice of Pharmacy (19th ed.) ed. A. R. Gennaro, Mack Publishing Company, Easton, Pa. 1995. Typically, an appropriate amount of pharmaceutically-acceptable salt is used in the formulation to render the formulation isotonic. Other examples of the pharmaceutically-acceptable carrier include, but are not limited to, saline, Ringer's solution and dextrose solution. The pH of the solution can be from about 5 to about 8, or from about 7 to about 7.5. Further carriers include sustained release preparations such as semi-permeable matrices of solid hydrophobic polymers containing the composition, which matrices are in the form of shaped articles, e.g., films, stents (which are implanted in vessels during an angioplasty procedure), liposomes or microparticles. It will be apparent to those persons skilled in the art that certain carriers may be more preferable depending upon, for instance, the route of administration and concentration of composition being administered. These most typically would be standard carriers for administration of drugs to humans, including solutions such as sterile water, saline, and buffered solutions at physiological pH.
Pharmaceutical compositions can also include carriers, thickeners, diluents, buffers, preservatives and the like, as long as the intended activity of the polypeptide, peptide, nucleic acid, vector of the invention is not compromised. Pharmaceutical compositions may also include one or more active ingredients (in addition to the composition of the invention) such as antimicrobial agents, anti-inflammatory agents, anesthetics, and the like. The pharmaceutical composition may be administered in a number of ways depending on whether local or systemic treatment is desired, and on the area to be treated.
Preparations of parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like.
Formulations for optical administration may include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids, or binders may be desirable. Some of the compositions may potentially be administered as a pharmaceutically acceptable acid- or base-addition salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, and organic bases such as mon-, di-, trialkyl and aryl amines and substituted ethanolamines.
D. Methods for Affecting LDL and VLDL
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected. The ApoE-mimicking peptide can be a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha. For example, the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein the synthetic ApoE-mimicking peptide is administered as a composition comprising the synthetic ApoE-mimicking peptide and a pharmaceutically acceptable carrier.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein binding of LDL to a cell of the subject is enhanced.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein degradation of LDL by a cell of the subject is increased.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein LDL cholesterol in the subject is lowered.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein binding of VLDL to a cell of the subject is enhanced.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein degradation of VLDL by a cell of the subject is increased.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein VLDL cholesterol in the subject is lowered.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein total plasma concentration of cholesterol in the subject is lowered.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein said synthetic ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range in between.
Disclosed are methods comprising administering any one of the disclosed synthetic ApoE-mimicking peptides to a subject, whereby plasma LDL, plasma VLDL, or both, are affected, wherein the subject has coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, and/or congestive heart failure, or bacterial infections.
E. Methods of Reducing Plasma Cholesterol
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides. The ApoE-mimicking peptide can be a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha. For example, the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein the synthetic ApoE-mimicking peptide is administered as a composition comprising the synthetic ApoE-mimicking peptide and a pharmaceutically acceptable carrier.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein binding of LDL to a cell of the subject is enhanced.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of LDL by a cell of the subject is increased.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein LDL cholesterol in the subject is lowered.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein binding of VLDL to a cell of the subject is enhanced.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein VLDL cholesterol in the subject is lowered.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein total plasma concentration of cholesterol in the subject is lowered.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein said synthetic ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range in between.
Disclosed are methods of reducing plasma cholesterol comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein the subject has coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, and/or congestive heart failure.
F. Methods of Treating Atherosclerosis
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides. The ApoE-mimicking peptide can be a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha. For example, the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein the synthetic ApoE-mimicking peptide is administered as a composition comprising the synthetic ApoE-mimicking peptide and a pharmaceutically acceptable carrier.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein binding of LDL to a cell of the subject is enhanced.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of LDL by a cell of the subject is increased.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein LDL cholesterol in the subject is lowered.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein binding of VLDL to a cell of the subject is enhanced.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein VLDL cholesterol in the subject is lowered.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein total plasma concentration of cholesterol in the subject is lowered.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein said synthetic ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range in between.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein the subject has coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, and/or congestive heart failure.
G. Methods for Treating Lipid Disorders
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof. The ApoE-mimicking peptide can be a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha. For example, the synthetic ApoE-mimicking peptide can be Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein the synthetic ApoE-mimicking peptide is administered as a composition comprising the synthetic ApoE-mimicking peptide and a pharmaceutically acceptable carrier.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein binding of LDL to a cell of the subject is enhanced.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein degradation of LDL by a cell of the subject is increased.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein LDL cholesterol in the subject is lowered.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein binding of VLDL to a cell of the subject is enhanced.
Disclosed are methods of treating atherosclerosis comprising administering to a subject an effective amount of a composition comprising any one of the disclosed synthetic ApoE-mimicking peptides, wherein degradation of VLDL by a cell of the subject is increased.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein VLDL cholesterol in the subject is lowered.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein total plasma concentration of cholesterol in the subject is lowered.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein said synthetic ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mg/kg, or any range in between.
Disclosed are methods of treating a subject with a lipid disorder comprising administering to the subject an effective amount of any one of the disclosed ApoE-mimicking peptides or a composition thereof, wherein the lipid disorder can be coronary artery disease, rheumatoid arthritis, systemic lupus, diabetes, Alzheimer's disease, PAD, cerebral vascular disease, diabetes-derived cardiovascular diseases, macular degeneration, and/or congestive heart failure.
H. Monoclonal Antibodies
Disclosed are monoclonal antibodies that specifically bind to any one of the synthetic ApoE-mimicking peptides described herein.
I. Dosing Regimens
Disclosed are dosing regimens comprising at least one treatment cycle of an effective amount of any of the disclosed Apo E-mimicking peptides followed by a rest phase. The rest phase of the dosing regimen is a period of time where the Apo E-mimicking peptide is not administered. The ApoE-mimicking peptide can be, but is not limited to, Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2.
Disclosed are dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase. Not only does an effective amount of Apo E-mimicking peptide result in sustained therapeutic effects, but it is also an amount sufficient to cause an acute beneficial effect. Thus, the effects of the Apo E-mimicking peptide can be measured and seen during the treatment cycle, at the end of the treatment cycle and during the rest phase. The sustained therapeutic effects are the therapeutic effects seen even after an acute cholesterol lowering effect is gone.
Disclosed herein are dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic, wherein the Apo E-mimicking peptide is not administered during the rest phase, wherein the treatment cycle comprises administration of an effective amount of the Apo E-mimicking peptide once a week for three months or wherein the treatment cycle comprises administration of an effective amount of the Apo E-mimicking peptide once every two weeks for up to 12 weeks.
Disclosed are dosing regimens comprising at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase, wherein the dosing regimen further comprises a second treatment cycle after the rest phase.
In one aspect, dosing regimens can comprise at least one treatment cycle followed by a rest phase, wherein the treatment cycle comprises administering an effective amount of a synthetic ApoE-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the Apo E-mimicking peptide is not administered during the rest phase, wherein the synthetic ApoE-mimicking peptide comprises an Ac-Aha.
Dosing regimens can further include a second treatment cycle after the rest phase. A second rest phase can occur after the second treatment cycle. In some instances a third, fourth, fifth, sixth, seventh, eighth, ninth or tenth treatment cycle can be administered wherein each treatment cycle is followed by a rest phase. In one aspect, the dosing regimen includes infinite treatment cycles, each followed by a rest phase. For example, a subject may be prescribed a dosing regimen that involves consecutive treatment cycles followed by rest phases for the duration of their life.
In one aspect, a second dosing regimen can be prescribed based on the re-occurrence of atherosclerotic lesions or other atherosclerosis factors. The second dosing regimen can be administered 1, 2, 3, 4, 5 years or more than 5 years after the initial dosing regimen was administered. The second dosing regimen can be the same as the initial dosing regimen or can be different. For example, the initial dosing regimen can be a three month treatment cycle followed by a one year rest phase. After the one year rest phase the subject can be tested and if atherosclerotic lesions are building up again then a second dosing regimen consisting of another three month treatment cycle followed by a rest phase or a six month treatment cycle followed by a rest phase can be prescribed. The dose of Apo E mimetic can vary between the initial dosing regimen and any additionally prescribed dosing regimens.
In some instances, the second dosing can be administered based on vasoresponsiveness, presence of isolated systolic hypertension, or exercise-induced angina determined in the subject after the first treatment. In some instances, the second dose can be administered based on the amount of plasma cholesterol. The frequency of administration can be altered depending on the need for reducing plasma cholesterol to minimize or eliminate the risk for any of the disorders disclosed herein.
1. Treatment Cycle
Treatment cycles can include the administration of different dosages of ApoE-mimicking peptide as well as administration at different time points. The ApoE-mimicking peptide can be administered for varying amounts of time for up to 6 months. In some instances, the administration can occur for up to one, two, three, four, five or six months. For example, the ApoE-mimicking peptide can be administered once a week for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks.
The length of time for each treatment cycle can vary depending on the amount of ApoE-mimicking peptide administered per dosage. A treatment cycle can include the administration of ApoE-mimicking peptide once, twice or three times a week. In some aspects, the ApoE-mimicking peptide can be administered daily. In some aspects, the ApoE-mimicking peptide can be administered once every two weeks or even once a month. In some instances, the Apo E mimetic can be administered every two weeks for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks. For example, the treatment cycle can include administering an ApoE-mimicking peptide once a week for four weeks or once every two weeks for up to six months. Thus, each treatment cycle includes an established length of time for administration as well as an established dosing schedule during that time frame.
In one aspect, more than one ApoE-mimicking peptide can be administered during the treatment cycles. The more than one ApoE-mimicking peptide can be formulated together or in separate compositions. In some instances, one or more Apo E mimetic is administered in combination with one or more other therapeutic agents, such as cholesterol lowering drugs.
2. Rest Phase
The disclosed dosing regimens can include at least one treatment cycle followed by a rest phase. The rest phase is a period of time wherein ApoE-mimicking peptide is not administered and the length of the period of time can vary. The length of the rest phase is dependent on how long the sustained therapeutic effects of the Apo E mimetic administered during the treatment cycle last. In some instances the rest phase can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some instances the rest phase can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. For example, the rest phase can be at least four weeks (one month).
One way to determine how long the rest phase should last is to test the subject to determine the progression of the atherosclerosis burden in the subject's arteries. If the atherosclerosis burden has progressed to a level that increases the risk of cardiovascular disease, then the subject can be prescribed a second dosing regimen. If the atherosclerosis burden is stable then the rest phase can be prolonged. The length of the reset phase can also be based on VLDL reduction, LDL reduction, glucose reduction, inflammation reduction, vasoresponsiveness, presence of isolated systolic hypertension, or exercise-induced angina, or amount of plasma cholesterol. Subjects can be tested on a regular basis. For example, a subject can be tested every 3, 6, 9, 12, 18, 24, 30 or 36 months.
In one aspect, the rest phase can be decreased or extended depending on the dose of ApoE-mimicking peptide administered and the reduction in atherosclerosis achieved during the treatment cycle. For example, the rest phase can be extended if the dose of ApoE-mimicking peptide during the treatment cycle is increased and the atherosclerosis burden is substantially reduced. The length of the rest phase can also vary based on the length of the treatment cycle. For instance, if a subject receives a certain dose of ApoE-mimicking peptide once a week for three months then the rest phase may be shorter than a subject that receives the same dose of Apo E mimetic once a week for six months.
Although an Apo E mimetic is not administered during the rest phase, an atherosclerosis therapeutic other than an Apo E mimetic can be administered during the rest phase. The atherosclerosis therapeutic other than an Apo E mimetic can be a conventional lipid lowering therapy, such as a statin, a bile acid sequestrant or a fibrate, or a novel anti-atherosclerosis therapeutic like a CETP inhibitor, a VLDL synthesis inhibitor, a PCSK9 inhibitor, and/or an arterial inflammation inhibitor. In other words, the atherosclerosis therapeutic other than an Apo E mimetic can be a conventional LDL lowering therapeutic or a HDL elevating therapeutic.
In some instances, the beneficial effects of the Apo E mimetic can still be present in a subject even after the treatment cycle is complete. In one instance, the half-life of the Apo E mimetic is less than 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 days. In some instances the Apo E mimetic is no longer detectable in a subject after the treatment cycle is complete. Thus, the long-term therapeutic effects are not from residual Apo E mimetic.
3. Dose
The dose or dosage of ApoE-mimicking peptide can vary depending on many factors, such as but not limited to, age, condition, sex and extent of the disease in the patient, route of administration, length of treatment cycle, or whether other drugs are included in the regimen, and can be determined by one of skill in the art.
Effective dosages can be determined empirically, and making such determinations is within the skill in the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the disease is treated. For example, the dosage can be an amount effective to provide therapeutic effects and provide or allow for sustained therapeutic effects even after the treatment (i.e. ApoE-mimicking peptide) is withdrawn. The therapeutic effects can be, but are not limited to, a reduction in atherosclerotic lesions, decrease in arterial stiffness, decrease in isolated systolic hypertension, increase in vasoresponsiveness or improvement in cardiac function. The therapeutic effects can be measured by markers of arterial inflammation such as, but not limited to, C-reactive protein. The therapeutic effects can be measured by atherosclerosis imaging techniques, including MRI, intravascular ultrasound, ultrafast imaging CT scans, B-mode ultrasonography, virtual histology intravascular ultrasound, optical coherence tomography, or other known methods.
The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. The dosage can be adjusted by the individual physician in the event of any counter-indications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
Suitable dosages include, but are not limited to amounts between 0.01 mg/kg and 20 mg/kg. For example, disclosed herein are methods involving administering one or more of the disclosed ApoE-mimicking peptide to a subject, wherein the ApoE-mimicking peptide is administered in an amount of about 0.01 mg/kg to about 20 mg/kg. For example, the concentration of the ApoE-mimicking peptide can be 0.01, 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg/kg.
The ApoE-mimicking peptide dose can be administered as a bolus injection or as an infusion over one or more hours.
J. Methods of Treating Using Dosing Regimens
Methods of treating acute coronary syndrome (ACS) or atherosclerosis comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle followed by a rest phase are provided. For example, the Apo E-mimicking peptide can be Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2. Thus, the disclosed methods involve administering an Apo E-mimicking peptide using one or more of the disclosed dosing regimens. Thus, any of the disclosed treatment cycles or rest phases can be used in the disclosed methods. The methods disclosed herein can allow for prolonged therapeutic effects even in the absence of the therapeutic. The disclosed methods can include the administration of an effective amount of Apo E mimetic. The effective amount of an Apo E mimetic can be an amount that allows for sustained therapeutic effects after the Apo E mimetic has been withdrawn.
Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase.
Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase, wherein the rest phase is at least four weeks.
Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase, further comprising a second treatment cycle after the rest phase. The second treatment cycle can be administered after a four week rest phase or one year from the beginning of the initial treatment cycle.
Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase, wherein an ACS therapeutic other than an Apo E-mimicking peptide is administered during the rest phase. The ACS therapeutic other than an Apo E-mimicking peptide can be a conventional LDL lowering therapy or HDL elevating therapy. A conventional LDL lowering therapy can be, but is not limited to, a statin. An HDL elevating therapy can be, but is not limited to, Apo A1 elevating drug, a CETP inhibitor, a phospholipase A2 inhibitor, an Apo A1 Milano, or an Apo A1 mimetic.
Disclosed herein are methods of treating atherosclerosis comprising administering to a subject an effective amount of an Apo E mimetic for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E mimetic to allow for a sustained therapeutic effect after withdrawal of the Apo E mimetic, wherein the Apo E mimetic consists of the Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2 peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo E mimetic is not administered during the rest phase.
Disclosed herein are methods of treating ACS comprising administering an effective amount of any one of the disclosed Apo E-mimicking peptides for at least one treatment cycle, wherein the treatment cycle comprises administering an effective amount of an Apo E-mimicking peptide to allow for a sustained therapeutic effect after withdrawal of the Apo E-mimicking peptide, wherein the treatment cycle is followed by a rest phase, wherein Apo-E mimicking peptide is not administered during the rest phase, wherein the treatment cycle comprises administration of an effective amount of an Apo E-mimicking peptide once a week for three months.
The disclosed methods of treating can occur at different times depending on the subject. In particular, treatment can occur in a subject considered to be of high, or high residual risk of a cardio- or cerebrovascular event. In one instance, the treatment can be initiated after a subject is stabilized following an acute coronary event. In one instance, the treatment can be initiated immediately after the acute coronary event, or 3, 6, 9, or 12 months after the acute coronary event. The treatment can be initiated following acute interventional cardiology procedures such as coronary artery bypass surgery (CABG), percutaneous coronary intervention (angioplasty, PCI), or implant of a stent into a coronary artery. Subjects considered as high risk can be those individuals that have homozygous familial hypercholesterolemia (FH), severe refractory FH, diabetes or an individual following acute coronary syndrome (ACS). In high risk subjects, treatment can be extended.
1. Treatment Cycle
The treatment cycle, as previously described with respect to the dosing regimens, can vary in length of time. The treatment cycle can be at least four weeks but can last up to six months. In one instance, the disclosed methods have a treatment cycle that involves the administration of an effective amount of an ApoE-mimicking peptide once a week for one month (four weeks), three months (12 weeks) or six months (24 weeks). A treatment cycle can include the administration of ApoE-mimicking peptide once, twice or three times a week. In some aspects, the ApoE-mimicking peptide can be administered daily. In some aspects, the ApoE-mimicking peptide can be administered once every two weeks or even once a month. In some instances, the ApoE-mimicking peptide can be administered every two weeks for 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 weeks. Each treatment cycle can include an established length of time for administration as well as an established dosing schedule during that time frame.
The methods can further include a second treatment cycle after the rest phase. In one aspect, the second treatment cycle can be administered after a four week rest phase. In another aspect, the second treatment cycle can be administered at least one year from the beginning of the initial treatment cycle.
2. Rest Phase
The rest phase, as previously described with regards to the dosing regimen, can be at least four weeks but can last for several years. The ApoE-mimicking peptide is not administered during the rest phase.
The length of the rest phase is dependent on how long the sustained therapeutic effects of the ApoE-mimicking peptide administered during the treatment cycle last. In some instances the rest phase can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. In some instances the rest phase can be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years. For example, the rest phase can be at least four weeks (one month).
In one aspect, the rest phase can be decreased or extended depending on the dose of ApoE-mimicking peptide administered during the treatment cycle. For example, the rest phase can be extended if the dose of ApoE-mimicking peptide during the treatment cycle is increased. The length of the rest phase can also vary based on the length of the treatment cycle. For instance, if a subject receives a certain dose of ApoE-mimicking peptide once a week for three months then the rest phase may be shorter than a subject that receives the same dose of ApoE-mimicking peptide once a week for six months.
Although an ApoE-mimicking peptide is not administered during the rest phase, an atherosclerosis therapeutic other than an ApoE-mimicking peptide can be administered during the rest phase. The atherosclerosis therapeutic other than an Apo E mimetic can be a conventional lipid lowering therapy, such as a statin, or bile acid sequestrant, and/or a therapeutic such as a PCSK9 inhibitor, a VLDL synthesis inhibitor and/or a CETP inhibitor.
3. Atherosclerosis
The combination of LDL accumulation in a vessel wall and an inflammatory response to the LDL's is responsible for initiating atherosclerosis. The LDL within the vessel wall becomes oxidized which damages the vessel wall and triggers an immune response. Immune cells, such as macrophages, are not able to process the oxidized-LDL and eventually rupture which leads to more oxidized cholesterol in the artery wall. This cycle continues which causes more and more damage to the vessel walls. The increase in cholesterol leads to plaques which ultimately results in hardening and narrowing of the vessel wall. The disclosed methods are useful for treating atherosclerosis and other lipid disorders.
K. Delivery
In the methods described herein, administration or delivery of the ApoE-mimicking peptides can be via a variety of mechanisms. As defined above, disclosed herein are methods of treating, dosing regimens and methods of using those dosing regimens to treat. The dosing regimens and methods include compositions containing any one or more of the polypeptides or nucleic acids described herein that can also include a carrier such as a pharmaceutically acceptable carrier. For example, disclosed are pharmaceutical compositions, comprising the ApoE-mimicking peptide disclosed herein, and a pharmaceutically acceptable carrier.
The disclosed ApoE-mimicking peptide can be in solution or in suspension (for example, incorporated into microparticles, liposomes, or cells). These compositions can be targeted to a particular cell type via antibodies, receptors, or receptor ligands. One of skill in the art knows how to make and use such targeting agents with the disclosed compositions. A targeting agent can be a vehicle such as an antibody conjugated liposomes; receptor mediated targeting of DNA through cell specific ligands, and highly specific retroviral targeting of cells in vivo. Any such vehicles can be part of the compositions herein. For example, targeting agents that direct the ApoE-mimicking peptide to the blood vessel walls can be included in the compositions.
Any suitable route of administration can be used for the disclosed compositions. Suitable routes of administration can, for example, include topical, enteral, local, systemic, or parenteral. For example, administration can be epicutaneous, inhalational, enema, conjunctival, eye drops, ear drops, alveolar, nasal, intranasal, enteral, oral, intraoral, transoral, intestinal, rectal, intrarectal, transrectal, injection, infusion, intravenous, intraarterial, intramuscular, intracerebral, intraventricular, intracerebroventricular, intracardiac, subcutaneous, intraosseous, intradermal, intrathecal, intraperitoneal, intravesical, intracavernosal, intramedullar, intraocular, intracranial, transdermal, transmucosal, transnasal, inhalational, intracisternal, epidural, peridural, intravitreal, etc. The disclosed compositions can be used in and with any other therapy.
Unlike typical peptide formulations, the peptides of this invention comprising D-form amino acids can be administered, even orally, without protection against proteolysis by stomach acid, etc. Nevertheless, in certain embodiments, peptide delivery can be enhanced by the use of protective excipients. This is typically accomplished either by complexing the polypeptide with a composition to render it resistant to acidic and enzymatic hydrolysis or by packaging the polypeptide in an appropriately resistant carrier such as a liposome. Means of protecting polypeptides for oral delivery are well known in the art (see, e.g., U.S. Pat. No. 5,391,377 describing lipid compositions for oral delivery of therapeutic agents).
Elevated serum half-life can be maintained by the use of sustained-release protein “packaging” systems. Such sustained release systems are well known to those of skill in the art. In one preferred embodiment, the ProLease biodegradable microsphere delivery system for proteins and peptides (Tracy (1998) Biotechnol. Prog., 14: 108; Johnson et al. (1996) Nature Med. 2: 795; Herbert et al. (1998), Pharmaceut. Res. 15, 357) a dry powder composed of biodegradable polymeric microspheres containing the active agent in a polymer matrix that can be compounded as a dry formulation with or without other agents.
The ProLease microsphere fabrication process was specifically designed to achieve a high encapsulation efficiency while maintaining integrity of the active agent. The process consists of (i) preparation of freeze-dried drug particles from bulk by spray freeze-drying the drug solution with stabilizing excipients, (ii) preparation of a drug-polymer suspension followed by sonication or homogenization to reduce the drug particle size, (iii) production of frozen drug-polymer microspheres by atomization into liquid nitrogen, (iv) extraction of the polymer solvent with ethanol, and (v) filtration and vacuum drying to produce the final dry-powder product. The resulting powder contains the solid form of the active agents, which is homogeneously and rigidly dispersed within porous polymer particles. The polymer most commonly used in the process, poly(lactide-co-glycolide) (PLG), is both biocompatible and biodegradable.
Encapsulation can be achieved at low temperatures (e.g., −40° C.). During encapsulation, the protein is maintained in the solid state in the absence of water, thus minimizing water-induced conformational mobility of the protein, preventing protein degradation reactions that include water as a reactant, and avoiding organic-aqueous interfaces where proteins may undergo denaturation. A preferred process uses solvents in which most proteins are insoluble, thus yielding high encapsulation efficiencies (e.g., greater than 95%).
In another embodiment, one or more components of the solution can be provided as a “concentrate”, e.g., in a storage container (e.g., in a premeasured volume) ready for dilution, or in a soluble capsule ready for addition to a volume of water.
The foregoing formulations and administration methods are intended to be illustrative and not limiting. It will be appreciated that, using the teaching provided herein, other suitable formulations and modes of administration can be readily devised.
1. Combination Therapy
In one aspect of the disclosed methods, the Apo E mimetics can be administered alone or in combination with one or more additional therapeutic agents. The additional therapeutic agents are selected based on the disease or symptom to be treated. A description of the various classes of suitable pharmacological agents and drugs may be found in Goodman and Gilman, The Pharmacological Basis of Therapeutics, (11th Ed., McGraw-Hill Publishing Co.) (2005). For example, pharmaceutical compositions containing Apo E mimetics can be administered in combination with one or more known therapeutic agents for treating atherosclerosis. Therapeutic agents for treating atherosclerosis include, but are not limited to, cholesterol-lowering agents, HDL elevating agents, blood pressure-lowering agents, blood thinning agents (i.e. medicines that prevent blood clots), anti-inflammatory agents, and anti-atherogenic agents. Examples of cholesterol-lowering agents include, but are not limited to, a cholesterol absorption inhibitor, a bile acid sequestrant, a fibrate, a PCSK9 inhibitor, a microsomal triglyceride transfer protein inhibitor, an apolipoprotein B synthesis inhibitor, or a CETP inhibitor.
The Apo E mimetics can be administered in conjunction with or followed by any of the disclosed additional therapeutics. The treatments can be administered in conjunction with or followed by LDL apheresis.
The combination therapies can include administering the Apo E mimetic and an additional therapeutic agent during the treatment cycle of a dosing regimen. The combination therapies can also include administering the Apo E mimetic during the treatment cycle and an additional therapeutic agent during the rest phase.
EXAMPLES
It is understood that the disclosed method and compositions are not limited to the particular methodology, protocols, and reagents described as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the method and compositions described herein. Such equivalents are intended to be encompassed by the following claims.
Example 1: Preparation and Analysis of Synthetic ApoE-mimicking Peptides Analogs
The synthetic ApoE-mimicking peptides used in the studies described in FIGS. 3-14 were prepared were prepared by standard Fmoc solid-phase peptide synthesis techniques. Various peptides and the rationale for preparation are shown in FIG. 1 . Representative analytical HPLC profiles of the synthesized peptides are shown in FIGS. 2A-2G.
Example 2: Effect of AEM Analogs in ApoE Null Mice
Studies showing the effects of various synthetic ApoE-mimicking peptides on plasma cholesterol levels are shown in FIGS. 3-14 .
Example 3: Effect of AEM Analogs in High-Sucrose Fed Rats
Male Sprague-Dawley rats were purchased from Charles River and fed a diet containing 65% sucrose for two weeks. The lipoprotein profile (FIG. 15 ) showed an increase of triglycerides. The rats weighed 370+/−2 Og at the time of administration of peptides. The peptides administered (5 mg/kg tail vein) were as follows: Ac-hE18A-NH2, Ac—[R]hE18A-NH2 and Ac-Aha-[R]hE18A-NH2 where hE refers to LRKLRKRLLR (SEQ ID NO:4) and [R]hE refers to LRRLRRRLLR (SEQ ID NO:6) and Aha refers to H2N—(CH2)5—COOH. Blood was drawn at the times indicated in graphs and after separating cells, plasma was analyzed for cholesterol, triglycerides and glucose levels. Plasma triglycerid levels at different time points are shown in FIG. 16 . Data were also obtained at 48 h post-administration of the peptide for plasma triglyceride (FIG. 17 ), cholesterol levels (FIG. 18 ), and plasma glucose levels (FIG. 19 ).
Example 4: Preparation and Analysis of Fatty Acid Containing Peptides
The following peptides were prepared: (1) octanoyl-LRRLRRRLLR-18A-NH2 (SEQ ID NO:625); (2) myristoyl-LRRLRRRLLR-18A-NH2 (SEQ ID NO:628); (3) oleoyl-LRRLRRRLLR-18A-NH2 (SEQ ID NO:634); (4) palmitoyl-LRRLRRRLLR-18A-NH2 (SEQ ID NO:629); and (5) Fish oil-LRRLRRRLLR-18A-NH2 (SEQ ID NO:647), in which fish oil was principally a mixture of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), with other components in small amounts.
The peptides were synthesized on a Rink amide resin (5 mM of the functional group present on 10 g of the resin was used). Suitable FMOC-amino acid derivatives were added using HBTu method of condensation (three couplings for each amino acid at 5×, 3×, and 2× for three couplings). After the last amino acid leucine (L) was added, the resin weighed approximately 40 g, indicating quantitative yield for the coupling of amino acids. Resin (2 g) was taken for each fatty acid and each fatty acid was added two times with 10× and 5× couplings using HBTu in DMF. The peptide was released from the resin using TFA:water:anisole:ethylenedithiol (95:2:2:1 by volume, 10 ml/G of the reagent) for 3.5 hr at room temperature. After filtration of the resin, the peptide was precipitated by adding ether, washed by centrifugation with ether three times. Peptide was first dialyzed and then purified by HPLC. Since fish oil derivative is known to contain mixture that was very difficult to purify, this was not purified but the ability of this peptide to reduce plasma cholesterol in apoE null mice was compared with other dialyzed peptides. Purification of peptides was achieved using C18 silica gel column, and FIGS. 20A-20E shows representative analytical HPLC profiles of the peptides (C-18 Vydac column-250×4.6 mm; solvent system was a gradient of water/acetonitrile (0.1% TFA), 35-70% in 12 minutes).
Example 5: Effect of Fatty Acid Containing Peptides in ApoE Null Mice
The effects of synthetic ApoE-mimicking peptides comprising a fatty acid moiety at the N-terminus of the peptide on plasma cholesterol are shown in FIGS. 21-31 .
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims (18)

We claim:
1. A synthetic apolipoprotein E(ApoE)-mimicking peptide comprising a receptor binding domain of ApoE and a lipid-associating peptide, wherein the synthetic ApoE-mimicking peptide comprises a fatty acid moiety, a ω-amino fatty acid moiety, or an acetylated ω-amino fatty acid moiety, wherein the lipid-associating peptide comprises a class A amphipathic helical domain, wherein the fatty acid moiety is a saturated fatty acid moiety, wherein the receptor binding domain of ApoE is on the N-terminus of the synthetic ApoE-mimicking peptide, and wherein the saturated fatty acid moiety, ω-amino fatty acid moiety, or acetylated ω-amino fatty acid moiety is at the N-terminus of the receptor binding domain of ApoE.
2. The peptide of claim 1, wherein the synthetic ApoE-mimicking peptide comprises the acetylated ω-amino fatty acid moiety.
3. The peptide of claim 2, wherein the acetylated ω-amino fatty acid moiety is Ac-Aha.
4. The peptide of claim 2, wherein the Ac-Aha is at the N-terminus of the peptide.
5. The peptide of claim 1, wherein the synthetic ApoE-mimicking peptide comprises the ω-amino fatty acid moiety.
6. The peptide of claim 5, wherein A synthetic apolipoprotein E(ApoE)-mimicking peptide comprising a lipid-associating peptide, a receptor-binding domain of ApoE at the N-terminus of the ApoE-mimicking peptide, and a w-amino fatty acid moiety at the N-terminus of the receptor-binding domain, wherein the lipid-associating peptide comprises a class A amphipathic helical domain, and the ω-amino fatty acid moiety is 4-amino-butanoyl, 6-amino-caproyl, 8-amino-octanoyl, 10-amino-decanoyl, 12-amino-lauroyl, 14-amino-myristoyl, 14-amino-myristoleoyl, 16-amino-palmitoyl, 18-amino-stearoyl, 18-amino-oleoyl, 16-amino-palmitoleoyl, 18-amino-linoleoyl, 18-amino- linolenoyl 18-amino-linolenoyl, or 20-amino-arachidonoyl.
7. The peptide of claim 6, wherein the ω-amino group is acetylated.
8. The peptide of claim 1, wherein the fatty acid moiety, the ω-amino fatty acid moiety, or the acetylated ω-amino fatty acid moiety is at the N-terminus of the peptide.
9. The peptide of claim 1, wherein the class A amphipathic-helical domain is DWLKAFYDKVAEKLKEAF (SEQ ID NO:5), DWLRAFYDKVAEKLREAF (SEQ ID NO:618), DWLRALYDKVAEKLREAL (SEQ ID NO:619), DLLRALYDKVAEKLREAW (SEQ ID NO:620), or FAEKLKEAVKDYFAKLWD (SEQ ID NO:616).
10. The peptide of claim 1, wherein said synthetic ApoE-mimicking peptide is protected using an amide group at the C-terminus.
11. The peptide of claim 1, wherein the receptor binding domain of ApoE is LRKLRKRLLR (SEQ ID NO:4), LRRLRRRLLR (SEQ ID NO:11), LRKMRKRLMR (SEQ ID NO:7), RLTRKRGLK (SEQ ID NO:13), LRRMRRRLMR (SEQ ID NO:621), or RLTRRRGK (SEQ ID NO:622).
12. The peptide of claim 1, wherein the synthetic ApoE-mimicking peptide is Ac-Aha-hE18A-NH2 or Ac-Aha-[R]hE18A-NH2.
13. A pharmaceutical composition, comprising the synthetic apolipoprotein E-mimicking peptide of claim 1 and a pharmaceutically acceptable carrier.
14. The peptide of claim 1, wherein the A synthetic ApoE-mimicking peptide that is butanoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 623); hexanoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 624); octanoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 625); decanoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 626); lauroyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 627); myristoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628); palmitoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 629); stearoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 630); palmitoleoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 631); arachidoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 632); behenoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 633); oleoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 634); ricinoleoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 635); linolenoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 636); vacceoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 637); gadoleoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 638); erucoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 639); cetoleoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 640); nervonoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 641); adrenoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 642); α-linolenoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 643); γ-linolenoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 644); EPA-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 645); DHA-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 646), 4-amino-butanoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 648); 6-amino-hexanoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 649); 8-amino-octanoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 650); 10-amino-decanoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 651); 12-amino-lauroyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 652); 14-amino-myristoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 653); 16-amino-palmitoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 654); 16-amino-palmitoleoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 655); 18-amino-stearoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 656); 18-amino-oleoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 657); 18-amino-linolenoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 658); or 20-amino-arachidoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2(SEQ ID NO: 659).
15. The synthetic ApoE-mimicking peptide of claim 14, wherein the synthetic ApoE-mimicking peptide is oleovl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 634).
16. The synthetic ApoE-mimicking peptide of claim 14, wherein the synthetic ApoE-mimicking peptide is octano 1-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SE ID NO: 625).
17. The synthetic ApoE-mimicking peptide of claim 14, wherein the synthetic ApoE-mimicking peptide is myristoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 628).
18. The synthetic ApoE-mimicking peptide of claim 14, wherein the synthetic ApoE-mimicking peptide is palmitoyl-LRRLRRRLLRDWLKAFYDKVAEKLKEAF-NH2 (SEQ ID NO: 629).
US17/748,682 2014-07-31 2015-07-20 APOE mimetic peptides and higher potency to clear plasma cholesterol Active USRE50320E1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/748,682 USRE50320E1 (en) 2014-07-31 2015-07-20 APOE mimetic peptides and higher potency to clear plasma cholesterol

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201462031585P 2014-07-31 2014-07-31
PCT/US2015/041162 WO2016018665A1 (en) 2014-07-31 2015-07-20 Apoe mimetic peptides and higher potency to clear plasma cholesterol
US15/329,735 US10653747B2 (en) 2014-07-31 2015-07-20 ApoE mimetic peptides and higher potency to clear plasma cholesterol
US17/748,682 USRE50320E1 (en) 2014-07-31 2015-07-20 APOE mimetic peptides and higher potency to clear plasma cholesterol

Publications (1)

Publication Number Publication Date
USRE50320E1 true USRE50320E1 (en) 2025-03-04

Family

ID=55218188

Family Applications (2)

Application Number Title Priority Date Filing Date
US15/329,735 Ceased US10653747B2 (en) 2014-07-31 2015-07-20 ApoE mimetic peptides and higher potency to clear plasma cholesterol
US17/748,682 Active USRE50320E1 (en) 2014-07-31 2015-07-20 APOE mimetic peptides and higher potency to clear plasma cholesterol

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US15/329,735 Ceased US10653747B2 (en) 2014-07-31 2015-07-20 ApoE mimetic peptides and higher potency to clear plasma cholesterol

Country Status (10)

Country Link
US (2) US10653747B2 (en)
EP (1) EP3189069B1 (en)
JP (2) JP7081923B2 (en)
CN (1) CN107074923B (en)
AU (1) AU2015298263B2 (en)
BR (1) BR112017001860A2 (en)
CA (1) CA2954475C (en)
IL (1) IL250302B (en)
MX (1) MX383117B (en)
WO (1) WO2016018665A1 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2753381T3 (en) * 2013-03-14 2020-04-08 Uab Research Foundation Apolipoprotein Mimetics and Uses thereof
JP7081923B2 (en) 2014-07-31 2022-06-07 ユーエイビー リサーチ ファンデーション Higher effectiveness for removing apoE mimetic peptides and plasma cholesterol
DK3362063T3 (en) 2015-10-14 2023-04-03 Massachusetts Eye & Ear Infirmary HIGH-DOSE STATINS FOR AGE-RELATED MACULAR DEGENERATION
WO2017120568A1 (en) * 2016-01-08 2017-07-13 Lipimetix Development, Inc. Apoe mimetic peptide compositions
CN110545836A (en) * 2017-01-24 2019-12-06 马克雷根有限公司 Treating Age-Related Macular Degeneration and Other Eye Diseases with Apolipoprotein Mimics
WO2018190896A1 (en) 2017-04-13 2018-10-18 Lipimetix Development, Inc. Apoe mimetic peptide compositions
TW202010752A (en) 2018-04-11 2020-03-16 美商立畢密蒂斯發展公司 APOE mimetic peptide compositions
WO2020096020A1 (en) 2018-11-08 2020-05-14 国立大学法人埼玉大学 Liposome-binding peptide, construct for producing liposome-binding peptide, and liposome
CN111617232B (en) * 2020-06-04 2023-04-18 安域生物科技(杭州)有限公司 Application of ApoE receptor protein short peptide blocker in Alzheimer disease
CN114940711B (en) * 2021-10-25 2023-05-12 中山大学 Apolipoprotein A-I mimetic peptides and uses thereof
CN119233984A (en) * 2022-05-05 2024-12-31 美国政府(由卫生和人类服务部的部长所代表) Short apolipoprotein E mimetic peptides and methods of use thereof
EP4712998A1 (en) * 2023-05-17 2026-03-25 The Medical College of Wisconsin Dual-domain peptide for depleting hmgb1 from the circulation via liver hspg system
WO2025147594A1 (en) * 2024-01-04 2025-07-10 University Of Florida Research Foundation, Incorporated Peptides and method of use in preparing nanodiscs

Citations (377)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US3767040A (en) 1971-03-01 1973-10-23 Minnesota Mining & Mfg Pressure-sensitive polyurethane adhesives
US4155913A (en) 1973-02-08 1979-05-22 Hoffmann-La Roche Inc. Thienotriazolodiazepine derivatives
EP0045665A1 (en) 1980-08-06 1982-02-10 Aktiebolaget Hässle Enzyme inhibitors
US4342566A (en) 1980-02-22 1982-08-03 Scripps Clinic & Research Foundation Solid phase anti-C3 assay for detection of immune complexes
US4428938A (en) 1981-06-12 1984-01-31 Richter Gedeon Vegyeszeti Gyar Rt. Peptides affecting the immune regulation and a process for their preparation
US4469863A (en) 1980-11-12 1984-09-04 Ts O Paul O P Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof
US4476301A (en) 1982-04-29 1984-10-09 Centre National De La Recherche Scientifique Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon
US4587044A (en) 1983-09-01 1986-05-06 The Johns Hopkins University Linkage of proteins to nucleic acids
JPS61126099A (en) 1984-05-15 1986-06-13 リサ−チ・コ−ポレイシヨン Amphoteric ion
US4605735A (en) 1983-02-14 1986-08-12 Wakunaga Seiyaku Kabushiki Kaisha Oligonucleotide derivatives
US4667025A (en) 1982-08-09 1987-05-19 Wakunaga Seiyaku Kabushiki Kaisha Oligonucleotide derivatives
US4684520A (en) 1984-04-09 1987-08-04 Seuref A.G. Pharmaceutical compositions having cerebral antianoxic and metabolic activities
US4762779A (en) 1985-06-13 1988-08-09 Amgen Inc. Compositions and methods for functionalizing nucleic acids
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4824941A (en) 1983-03-10 1989-04-25 Julian Gordon Specific antibody to the native form of 2'5'-oligonucleotides, the method of preparation and the use as reagents in immunoassays or for binding 2'5'-oligonucleotides in biological systems
US4828979A (en) 1984-11-08 1989-05-09 Life Technologies, Inc. Nucleotide analogs for nucleic acid labeling and detection
US4835263A (en) 1983-01-27 1989-05-30 Centre National De La Recherche Scientifique Novel compounds containing an oligonucleotide sequence bonded to an intercalating agent, a process for their synthesis and their use
US4845205A (en) 1985-01-08 1989-07-04 Institut Pasteur 2,N6 -disubstituted and 2,N6 -trisubstituted adenosine-3'-phosphoramidites
US4868116A (en) 1985-07-05 1989-09-19 Whitehead Institute For Biomedical Research Introduction and expression of foreign genetic material in epithelial cells
US4876335A (en) 1986-06-30 1989-10-24 Wakunaga Seiyaku Kabushiki Kaisha Poly-labelled oligonucleotide derivative
US4877611A (en) 1986-04-15 1989-10-31 Ribi Immunochem Research Inc. Vaccine containing tumor antigens and adjuvants
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4904582A (en) 1987-06-11 1990-02-27 Synthetic Genetics Novel amphiphilic nucleic acid conjugates
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US4948882A (en) 1983-02-22 1990-08-14 Syngene, Inc. Single-stranded labelled oligonucleotides, reactive monomers and methods of synthesis
US4958013A (en) 1989-06-06 1990-09-18 Northwestern University Cholesteryl modified oligonucleotides
US4980286A (en) 1985-07-05 1990-12-25 Whitehead Institute For Biomedical Research In vivo introduction and expression of foreign genetic material in epithelial cells
US4981957A (en) 1984-07-19 1991-01-01 Centre National De La Recherche Scientifique Oligonucleotides with modified phosphate and modified carbohydrate moieties at the respective chain termini
US5023243A (en) 1981-10-23 1991-06-11 Molecular Biosystems, Inc. Oligonucleotide therapeutic agent and method of making same
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5082830A (en) 1988-02-26 1992-01-21 Enzo Biochem, Inc. End labeled nucleotide probe
US5109124A (en) 1988-06-01 1992-04-28 Biogen, Inc. Nucleic acid probe linked to a label having a terminal cysteine
US5112963A (en) 1987-11-12 1992-05-12 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Modified oligonucleotides
US5118800A (en) 1983-12-20 1992-06-02 California Institute Of Technology Oligonucleotides possessing a primary amino group in the terminal nucleotide
US5118802A (en) 1983-12-20 1992-06-02 California Institute Of Technology DNA-reporter conjugates linked via the 2' or 5'-primary amino group of the 5'-terminal nucleoside
US5130302A (en) 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5135917A (en) 1990-07-12 1992-08-04 Nova Pharmaceutical Corporation Interleukin receptor expression inhibiting antisense oligonucleotides
US5138045A (en) 1990-07-27 1992-08-11 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5168053A (en) 1989-03-24 1992-12-01 Yale University Cleavage of targeted RNA by RNAase P
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5176996A (en) 1988-12-20 1993-01-05 Baylor College Of Medicine Method for making synthetic oligonucleotides which bind specifically to target sites on duplex DNA molecules, by forming a colinear triplex, the synthetic oligonucleotides and methods of use
US5177196A (en) 1990-08-16 1993-01-05 Microprobe Corporation Oligo (α-arabinofuranosyl nucleotides) and α-arabinofuranosyl precursors thereof
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5188897A (en) 1987-10-22 1993-02-23 Temple University Of The Commonwealth System Of Higher Education Encapsulated 2',5'-phosphorothioate oligoadenylates
US5214134A (en) 1990-09-12 1993-05-25 Sterling Winthrop Inc. Process of linking nucleosides with a siloxane bridge
US5214136A (en) 1990-02-20 1993-05-25 Gilead Sciences, Inc. Anthraquinone-derivatives oligonucleotides
US5216141A (en) 1988-06-06 1993-06-01 Benner Steven A Oligonucleotide analogs containing sulfur linkages
US5218105A (en) 1990-07-27 1993-06-08 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5235033A (en) 1985-03-15 1993-08-10 Anti-Gene Development Group Alpha-morpholino ribonucleoside derivatives and polymers thereof
US5245022A (en) 1990-08-03 1993-09-14 Sterling Drug, Inc. Exonuclease resistant terminally substituted oligonucleotides
US5254469A (en) 1989-09-12 1993-10-19 Eastman Kodak Company Oligonucleotide-enzyme conjugate that can be used as a probe in hybridization assays and polymerase chain reaction procedures
US5258506A (en) 1984-10-16 1993-11-02 Chiron Corporation Photolabile reagents for incorporation into oligonucleotide chains
US5262536A (en) 1988-09-15 1993-11-16 E. I. Du Pont De Nemours And Company Reagents for the preparation of 5'-tagged oligonucleotides
US5264423A (en) 1987-03-25 1993-11-23 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
US5264564A (en) 1989-10-24 1993-11-23 Gilead Sciences Oligonucleotide analogs with novel linkages
US5264562A (en) 1989-10-24 1993-11-23 Gilead Sciences, Inc. Oligonucleotide analogs with novel linkages
US5272250A (en) 1992-07-10 1993-12-21 Spielvogel Bernard F Boronated phosphoramidate compounds
WO1993025581A1 (en) 1992-06-12 1993-12-23 N.V. Innogenetics S.A. New peptides and proteins, process for their preparation and their use as cholesterol acceptors
US5276019A (en) 1987-03-25 1994-01-04 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
US5278302A (en) 1988-05-26 1994-01-11 University Patents, Inc. Polynucleotide phosphorodithioates
US5292873A (en) 1989-11-29 1994-03-08 The Research Foundation Of State University Of New York Nucleic acids labeled with naphthoquinone probe
US5294533A (en) 1988-07-05 1994-03-15 Baylor College Of Medicine Antisense oligonucleotide antibiotics complementary to the macromolecular synthesis operon, methods of treating bacterial infections and methods for identification of bacteria
US5298490A (en) 1988-05-19 1994-03-29 Immunobiology Research Institute, Inc. Tetra and penta-peptides useful in regulating the immune system
US5317098A (en) 1986-03-17 1994-05-31 Hiroaki Shizuya Non-radioisotope tagging of fragments
US5319080A (en) 1991-10-17 1994-06-07 Ciba-Geigy Corporation Bicyclic nucleosides, oligonucleotides, process for their preparation and intermediates
US5321131A (en) 1990-03-08 1994-06-14 Hybridon, Inc. Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling
US5334711A (en) 1991-06-20 1994-08-02 Europaisches Laboratorium Fur Molekularbiologie (Embl) Synthetic catalytic oligonucleotide structures
US5344822A (en) 1992-08-12 1994-09-06 The Rogosin Institute Methods useful in endotoxin prophylaxis and therapy
US5359044A (en) 1991-12-13 1994-10-25 Isis Pharmaceuticals Cyclobutyl oligonucleotide surrogates
US5358934A (en) 1992-12-11 1994-10-25 The United States Of America As Represented By The Secretary Of Agriculture Materials and methods for control of pests
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
US5371241A (en) 1991-07-19 1994-12-06 Pharmacia P-L Biochemicals Inc. Fluorescein labelled phosphoramidites
US5391723A (en) 1989-05-31 1995-02-21 Neorx Corporation Oligonucleotide conjugates
US5391377A (en) 1990-10-19 1995-02-21 Cortecs Limited Biphasic release formations for lipophilic acids
US5399676A (en) 1989-10-23 1995-03-21 Gilead Sciences Oligonucleotides with inverted polarity
EP0643965A1 (en) 1993-09-20 1995-03-22 Kos Pharmaceuticals, Inc. Nicotinic acid compositions for treating hyperlipidemia
US5405939A (en) 1987-10-22 1995-04-11 Temple University Of The Commonwealth System Of Higher Education 2',5'-phosphorothioate oligoadenylates and their covalent conjugates with polylysine
US5405938A (en) 1989-12-20 1995-04-11 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5414077A (en) 1990-02-20 1995-05-09 Gilead Sciences Non-nucleoside linkers for convenient attachment of labels to oligonucleotides using standard synthetic methods
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
US5436330A (en) 1989-12-19 1995-07-25 Agency Of Industrial Science & Technology Hammerhead ribozymes with enhanced stability provided by an additional 3' ha
US5446137A (en) 1993-12-09 1995-08-29 Syntex (U.S.A.) Inc. Oligonucleotides containing 4'-substituted nucleotides
US5451463A (en) 1989-08-28 1995-09-19 Clontech Laboratories, Inc. Non-nucleoside 1,3-diol reagents for labeling synthetic oligonucleotides
US5455233A (en) 1989-11-30 1995-10-03 University Of North Carolina Oligoribonucleoside and oligodeoxyribonucleoside boranophosphates
US5457135A (en) 1992-05-08 1995-10-10 Baranowitz; Steven Treatment of age related macular degeneration with beta-carotene
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
US5466677A (en) 1993-03-06 1995-11-14 Ciba-Geigy Corporation Dinucleoside phosphinates and their pharmaceutical compositions
US5466786A (en) 1989-10-24 1995-11-14 Gilead Sciences 2'modified nucleoside and nucleotide compounds
US5470967A (en) 1990-04-10 1995-11-28 The Dupont Merck Pharmaceutical Company Oligonucleotide analogs with sulfamate linkages
US5473039A (en) 1989-08-18 1995-12-05 The Scripps Research Institute Polypeptide analogs of apolipoprotein E, diagnostic systems and methods using the analogs
US5476925A (en) 1993-02-01 1995-12-19 Northwestern University Oligodeoxyribonucleotides including 3'-aminonucleoside-phosphoramidate linkages and terminal 3'-amino groups
US5476766A (en) 1990-06-11 1995-12-19 Nexstar Pharmaceuticals, Inc. Ligands of thrombin
US5480869A (en) 1990-01-09 1996-01-02 The Regents Of The University Of California Anti-inflammatory peptide analogs and treatment to inhibit vascular leakage in injured tissues
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
US5486603A (en) 1990-01-08 1996-01-23 Gilead Sciences, Inc. Oligonucleotide having enhanced binding affinity
US5489677A (en) 1990-07-27 1996-02-06 Isis Pharmaceuticals, Inc. Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
US5503978A (en) 1990-06-11 1996-04-02 University Research Corporation Method for identification of high affinity DNA ligands of HIV-1 reverse transcriptase
US5508060A (en) 1993-02-11 1996-04-16 Minnesota Mining And Manufacturing Company Method of polymer impregnation
US5510475A (en) 1990-11-08 1996-04-23 Hybridon, Inc. Oligonucleotide multiple reporter precursors
US5512667A (en) 1990-08-28 1996-04-30 Reed; Michael W. Trifunctional intermediates for preparing 3'-tailed oligonucleotides
US5512439A (en) 1988-11-21 1996-04-30 Dynal As Oligonucleotide-linked magnetic particles and uses thereof
US5514785A (en) 1990-05-11 1996-05-07 Becton Dickinson And Company Solid supports for nucleic acid hybridization assays
US5519126A (en) 1988-03-25 1996-05-21 University Of Virginia Alumni Patents Foundation Oligonucleotide N-alkylphosphoramidates
US5519134A (en) 1994-01-11 1996-05-21 Isis Pharmaceuticals, Inc. Pyrrolidine-containing monomers and oligomers
US5525465A (en) 1987-10-28 1996-06-11 Howard Florey Institute Of Experimental Physiology And Medicine Oligonucleotide-polyamide conjugates and methods of production and applications of the same
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US5539082A (en) 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5541307A (en) 1990-07-27 1996-07-30 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogs and solid phase synthesis thereof
US5543293A (en) 1990-06-11 1996-08-06 Nexstar Pharmaceuticals, Inc. DNA ligands of thrombin
US5545730A (en) 1984-10-16 1996-08-13 Chiron Corporation Multifunctional nucleic acid monomer
US5550111A (en) 1984-07-11 1996-08-27 Temple University-Of The Commonwealth System Of Higher Education Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof
US5552540A (en) 1987-06-24 1996-09-03 Howard Florey Institute Of Experimental Physiology And Medicine Nucleoside derivatives
US5561225A (en) 1990-09-19 1996-10-01 Southern Research Institute Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
US5565552A (en) 1992-01-21 1996-10-15 Pharmacyclics, Inc. Method of expanded porphyrin-oligonucleotide conjugate synthesis
US5567811A (en) 1990-05-03 1996-10-22 Amersham International Plc Phosphoramidite derivatives, their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides
US5571799A (en) 1991-08-12 1996-11-05 Basco, Ltd. (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response
US5574142A (en) 1992-12-15 1996-11-12 Microprobe Corporation Peptide linkers for improved oligonucleotide delivery
US5576427A (en) 1993-03-30 1996-11-19 Sterling Winthrop, Inc. Acyclic nucleoside analogs and oligonucleotide sequences containing them
US5578718A (en) 1990-01-11 1996-11-26 Isis Pharmaceuticals, Inc. Thiol-derivatized nucleosides
US5579250A (en) 1990-12-14 1996-11-26 Balaji; Vitukudi N. Method of rational drug design based on AB initio computer simulation of conformational features of peptides
US5580967A (en) 1994-05-13 1996-12-03 The Scripps Research Institute Optimized catalytic DNA-cleaving ribozymes
US5580731A (en) 1994-08-25 1996-12-03 Chiron Corporation N-4 modified pyrimidine deoxynucleotides and oligonucleotide probes synthesized therewith
US5580737A (en) 1990-06-11 1996-12-03 Nexstar Pharmaceuticals, Inc. High-affinity nucleic acid ligands that discriminate between theophylline and caffeine
US5585481A (en) 1987-09-21 1996-12-17 Gen-Probe Incorporated Linking reagents for nucleotide probes
US5587361A (en) 1991-10-15 1996-12-24 Isis Pharmaceuticals, Inc. Oligonucleotides having phosphorothioate linkages of high chiral purity
US5587371A (en) 1992-01-21 1996-12-24 Pharmacyclics, Inc. Texaphyrin-oligonucleotide conjugates
US5591722A (en) 1989-09-15 1997-01-07 Southern Research Institute 2'-deoxy-4'-thioribonucleosides and their antiviral activity
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
US5595873A (en) 1994-05-13 1997-01-21 The Scripps Research Institute T. thermophila group I introns that cleave amide bonds
US5595726A (en) 1992-01-21 1997-01-21 Pharmacyclics, Inc. Chromophore probe for detection of nucleic acid
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5595973A (en) 1994-09-12 1997-01-21 Biomeasure Incorporated Protection of hemopoietic cells during chemotherapy or radiotherapy
US5596086A (en) 1990-09-20 1997-01-21 Gilead Sciences, Inc. Modified internucleoside linkages having one nitrogen and two carbon atoms
US5597696A (en) 1994-07-18 1997-01-28 Becton Dickinson And Company Covalent cyanine dye oligonucleotide conjugates
US5597909A (en) 1994-08-25 1997-01-28 Chiron Corporation Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use
US5599928A (en) 1994-02-15 1997-02-04 Pharmacyclics, Inc. Texaphyrin compounds having improved functionalization
US5602240A (en) 1990-07-27 1997-02-11 Ciba Geigy Ag. Backbone modified oligonucleotide analogs
US5608046A (en) 1990-07-27 1997-03-04 Isis Pharmaceuticals, Inc. Conjugated 4'-desmethyl nucleoside analog compounds
US5610300A (en) 1992-07-01 1997-03-11 Ciba-Geigy Corporation Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use and intermediates
US5610289A (en) 1990-07-27 1997-03-11 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogues
US5614617A (en) 1990-07-27 1997-03-25 Isis Pharmaceuticals, Inc. Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression
US5616466A (en) 1993-11-05 1997-04-01 Cantor; Glenn H. Ribozyme-mediated inhibition of bovine leukemia virus
US5618704A (en) 1990-07-27 1997-04-08 Isis Pharmacueticals, Inc. Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling
US5623070A (en) 1990-07-27 1997-04-22 Isis Pharmaceuticals, Inc. Heteroatomic oligonucleoside linkages
US5625050A (en) 1994-03-31 1997-04-29 Amgen Inc. Modified oligonucleotides and intermediates useful in nucleic acid therapeutics
US5624824A (en) 1989-03-24 1997-04-29 Yale University Targeted cleavage of RNA using eukaryotic ribonuclease P and external guide sequence
US5627053A (en) 1994-03-29 1997-05-06 Ribozyme Pharmaceuticals, Inc. 2'deoxy-2'-alkylnucleotide containing nucleic acid
US5627158A (en) 1990-11-02 1997-05-06 Cho-Chung; Yoon S. Antisense oligonucleotides of human regulatory subunit RI-.sub.α of camp dependent protein kinases for the treatment of cancer
US5631146A (en) 1995-01-19 1997-05-20 The General Hospital Corporation DNA aptamers and catalysts that bind adenosine or adenosine-5'-phosphates and methods for isolation thereof
US5631115A (en) 1992-07-02 1997-05-20 Sankyo Company, Limited Looped, hairpin ribozyme
US5631280A (en) 1995-03-29 1997-05-20 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US5633360A (en) 1992-04-14 1997-05-27 Gilead Sciences, Inc. Oligonucleotide analogs capable of passive cell membrane permeation
US5633133A (en) 1994-07-14 1997-05-27 Long; David M. Ligation with hammerhead ribozymes
US5639873A (en) 1992-02-05 1997-06-17 Centre National De La Recherche Scientifique (Cnrs) Oligothionucleotides
US5641754A (en) 1994-01-10 1997-06-24 The Board Of Regents Of The University Of Nebraska Antisense oligonucleotide compositions for selectively killing cancer cells
US5645985A (en) 1991-11-26 1997-07-08 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
US5646020A (en) 1992-05-14 1997-07-08 Ribozyme Pharmaceuticals, Inc. Hammerhead ribozymes for preferred targets
US5646265A (en) 1990-01-11 1997-07-08 Isis Pharmceuticals, Inc. Process for the preparation of 2'-O-alkyl purine phosphoramidites
US5646031A (en) 1995-05-16 1997-07-08 Northern Illinois University SArMV and sCYMVI hairpin ribozymes
US5646042A (en) 1992-08-26 1997-07-08 Ribozyme Pharmaceuticals, Inc. C-myb targeted ribozymes
US5650316A (en) 1994-06-06 1997-07-22 Research Development Foundation Uses of triplex forming oligonucleotides for the treatment of human diseases
US5652094A (en) 1992-01-31 1997-07-29 University Of Montreal Nucleozymes
US5652107A (en) 1993-01-15 1997-07-29 The Public Health Research Institute Of The City Of New York, Inc. Diagnostic assays and kits for RNA using RNA binary probes and a ribozyme ligase
US5658873A (en) 1993-04-10 1997-08-19 Degussa Aktiengesellschaft Coated sodium percarbonate particles, a process for their production and detergent, cleaning and bleaching compositions containing them
US5663312A (en) 1993-03-31 1997-09-02 Sanofi Oligonucleotide dimers with amide linkages replacing phosphodiester linkages
US5670633A (en) 1990-01-11 1997-09-23 Isis Pharmaceuticals, Inc. Sugar modified oligonucleotides that detect and modulate gene expression
WO1997036927A1 (en) 1996-03-29 1997-10-09 Dario Boffelli Amphipathic molecules as cholesterol and other lipid uptake inhibitors
US5677437A (en) 1990-07-27 1997-10-14 Isis Pharmaceuticals, Inc. Heteroatomic oligonucleoside linkages
US5677439A (en) 1990-08-03 1997-10-14 Sanofi Oligonucleotide analogues containing phosphate diester linkage substitutes, compositions thereof, and precursor dinucleotide analogues
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5683874A (en) 1991-03-27 1997-11-04 Research Corporation Technologies, Inc. Single-stranded circular oligonucleotides capable of forming a triplex with a target sequence
US5683902A (en) 1994-05-13 1997-11-04 Northern Illinois University Human papilloma virus inhibition by a hairpin ribozyme
US5683873A (en) 1995-01-13 1997-11-04 Innovir Laboratories, Inc. EGS-mediated inactivation of target RNA
US5688941A (en) 1990-07-27 1997-11-18 Isis Pharmaceuticals, Inc. Methods of making conjugated 4' desmethyl nucleoside analog compounds
US5688670A (en) 1994-09-01 1997-11-18 The General Hospital Corporation Self-modifying RNA molecules and methods of making
US5693773A (en) 1995-06-07 1997-12-02 Hybridon Incorporated Triplex-forming antisense oligonucleotides having abasic linkers targeting nucleic acids comprising mixed sequences of purines and pyrimidines
US5693535A (en) 1992-05-14 1997-12-02 Ribozyme Pharmaceuticals, Inc. HIV targeted ribozymes
US5700922A (en) 1991-12-24 1997-12-23 Isis Pharmaceuticals, Inc. PNA-DNA-PNA chimeric macromolecules
US5712384A (en) 1994-01-05 1998-01-27 Gene Shears Pty Ltd. Ribozymes targeting retroviral packaging sequence expression constructs and recombinant retroviruses containing such constructs
US5714331A (en) 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
US5719262A (en) 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
US5721138A (en) 1992-12-15 1998-02-24 Sandford University Apolipoprotein(A) promoter and regulatory sequence constructs and methods of use
US5721367A (en) 1990-08-29 1998-02-24 Pharming B.V. Homologous recombination in mammalian cells
WO1998009602A2 (en) 1996-09-05 1998-03-12 The Uab Research Foundation Anti-atherosclerotic peptides and a transgenic mouse model of atherosclerosis
US5728521A (en) 1989-03-24 1998-03-17 Yale University Targeted cleavage of RNA using eukaryotic ribonuclease P and external guide sequence
US5731295A (en) 1992-12-07 1998-03-24 Ribozyme Pharmaceuticals, Inc. Method of reducing stromelysin RNA via ribozymes
US5731424A (en) 1990-06-11 1998-03-24 Nexstar Pharmaceuticals, Inc. High affinity TGFβ nucleic acid ligands and inhibitors
US5733549A (en) 1992-08-14 1998-03-31 Shino-Test Corporation Peptides including amino acid sequences selected from lipoprotein (a) and apolipoprotein (a), antibodies recognizing these amino acid sequences, and methods of determination using these antibodies
US5770576A (en) 1989-08-30 1998-06-23 Cytran, Inc. Pharmaceutical dipeptide compositions and methods of use thereof: systemic toxicity
US5770715A (en) 1995-03-22 1998-06-23 Toagosei Co., Ltd. Hammerhead-like nucleic acid analogues and their synthesis
US5780228A (en) 1990-06-11 1998-07-14 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands to lectins
US5780607A (en) 1995-10-13 1998-07-14 Hoffmann-La Roche Inc. Antisense oligomers
US5786138A (en) 1993-01-29 1998-07-28 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Hyperstabilizing antisense nucleic acid binding agents
US5792613A (en) 1996-06-12 1998-08-11 The Curators Of The University Of Missouri Method for obtaining RNA aptamers based on shape selection
US5795721A (en) 1990-06-11 1998-08-18 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of ICP4
US5800758A (en) 1997-09-16 1998-09-01 Kimberly-Clark Worldwide, Inc. Process for making microporous films with improved properties
US5804440A (en) 1992-09-30 1998-09-08 The Scripps Research Institute Human neutralizing monoclonal antibodies to human immunodeficiency virus
US5807718A (en) 1994-12-02 1998-09-15 The Scripps Research Institute Enzymatic DNA molecules
US5811300A (en) 1992-12-07 1998-09-22 Ribozyme Pharmaceuticals, Inc. TNF-α ribozymes
US5814467A (en) 1990-06-07 1998-09-29 The Scripps Research Institute APO AI polypeptides, diagnostic methods and systems for quantifying APO AI, and therapeutic methods
US5834185A (en) 1986-10-28 1998-11-10 Johns Hopkins University Formation of triple helix complexes of single stranded nucleic acids using nucleoside oligomers which comprise pyrimidine analogs, triple helix complexes formed thereby and oligomers used in their formation
US5837243A (en) 1995-06-07 1998-11-17 Medarex, Inc. Therapeutic compounds comprised of anti-Fc receptor antibodies
US5837855A (en) 1994-10-11 1998-11-17 Ribozyme Pharmaceutical, Inc. Hairpin ribozymes
US5843708A (en) 1988-01-05 1998-12-01 Ciba-Geigy Corporation Chimeric antibodies
US5846713A (en) 1990-06-11 1998-12-08 Nexstar Pharmaceuticals, Inc. High affinity HKGF nucleic acid ligands and inhibitors
US5849903A (en) 1995-11-21 1998-12-15 Icn Pharmaceuticals, Inc. Antisense oligonucleotides for IL-8 and IL-8 receptor
US5854238A (en) 1995-09-09 1998-12-29 Hoffmann-La Roche Inc. Use of a thienotriazolodiazephine to increase apolipoprotein A-I levels
US5856188A (en) 1988-09-20 1999-01-05 The Board Of Regents For Northern Illinois University Of Dekalb Hairpin ribozymes
US5856463A (en) 1995-09-18 1999-01-05 Prydz; Hans Peter Blankenborg PSKH-1 ribozymes
US5856103A (en) 1994-10-07 1999-01-05 Board Of Regents The University Of Texas Method for selectively ranking sequences for antisense targeting
US5858660A (en) 1994-09-20 1999-01-12 Nexstar Pharmaceuticlas, Inc. Parallel selex
US5861254A (en) 1997-01-31 1999-01-19 Nexstar Pharmaceuticals, Inc. Flow cell SELEX
US5861288A (en) 1993-10-18 1999-01-19 Ribozyme Pharmaceuticals, Inc. Catalytic DNA
US5864026A (en) 1990-06-11 1999-01-26 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: tissue selex
US5869641A (en) 1990-06-11 1999-02-09 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of CD4
US5869253A (en) 1992-05-14 1999-02-09 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting hepatitis C virus replication
US5869246A (en) 1994-10-14 1999-02-09 Taiho Pharmaceutical Co., Ltd. Triplex Oligonucleotides targeted to p120
US5874566A (en) 1996-10-25 1999-02-23 Hisamitsu Pharmaceutical Co. Inc. Il-15 triplex oligonucleotides
US5877021A (en) 1995-07-07 1999-03-02 Ribozyme Pharmaceuticals, Inc. B7-1 targeted ribozymes
US5877153A (en) 1996-06-11 1999-03-02 Commonwealth Biotechnologies Inc. Heparin-binding peptides
US5877162A (en) 1996-03-14 1999-03-02 Innovir Laboratories, Inc. Short external guide sequences
US5877022A (en) 1994-09-23 1999-03-02 Ribozyme Pharmaceuticals, Inc Ribozymes targeted to APO(a) RNA
US5891684A (en) 1992-10-15 1999-04-06 Ribozyme Pharmaceuticals, Inc. Base-modified enzymatic nucleic acid
US5891683A (en) 1993-09-02 1999-04-06 Ribozyme Pharmaceuticals, Inc. Non-nucleotide containing enzymatic nucleic acid
WO1999016409A2 (en) 1997-09-29 1999-04-08 Dasseux Jean Louis Gene therapy approaches to supply apolipoprotein a-i agonists and their use to treat dyslipidemic disorders
WO1999016408A2 (en) 1997-09-29 1999-04-08 Dasseux Jean Louis Apolipoprotein a-i agonists and their use to treat dyslipidemic disorders
US5910408A (en) 1995-06-07 1999-06-08 The General Hospital Corporation Catalytic DNA having ligase activity
US5919772A (en) 1993-12-01 1999-07-06 Mcgill University Antisense oligonucleotides having tumorigenicity-inhibiting activity
US5939598A (en) 1990-01-12 1999-08-17 Abgenix, Inc. Method of making transgenic mice lacking endogenous heavy chains
US5955590A (en) 1996-07-15 1999-09-21 Worcester Foundation For Biomedical Research Conjugates of minor groove DNA binders with antisense oligonucleotides
WO1999047566A1 (en) 1998-03-17 1999-09-23 The Uab Research Foundation Synthetic peptides that enhance ldl uptake
US5958691A (en) 1990-06-11 1999-09-28 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands containing modified nucleotides
US5962426A (en) 1993-06-25 1999-10-05 Yale University Triple-helix forming oligonucleotides for targeted mutagenesis
US5972699A (en) 1992-05-14 1999-10-26 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting herpes simplex virus replication
US5985621A (en) 1994-03-29 1999-11-16 Ribozyme Pharmaceuticals, Inc. 2'-deoxy-2'-alkylnucleotide containing nucleic acid
US5989906A (en) 1992-05-14 1999-11-23 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting P-glycoprotein (mdr-1-gene)
US5989908A (en) 1994-09-12 1999-11-23 City Of Hope Modulation of drug and radiation resistant genes
US5990088A (en) 1993-06-04 1999-11-23 The United States Of America As Represented By The Department Of Health And Human Services Method for treating kaposi's sarcoma with antisense oligonucleotides
US5990081A (en) 1995-03-03 1999-11-23 Esperion Therapeutics, Inc. Purified APO A and APO E compounds and methods for using them
US5994320A (en) 1995-02-06 1999-11-30 Regents Of The University Of Minnesota Antisense oligonucleotides and methods for treating central nervous system tumors
US5998602A (en) 1996-02-15 1999-12-07 The Cleveland Clinic Fouindation And Government RNase L activators and antisense oligonucleotides effective to treat RSV infections
US5998203A (en) 1996-04-16 1999-12-07 Ribozyme Pharmaceuticals, Inc. Enzymatic nucleic acids containing 5'-and/or 3'-cap structures
US5998193A (en) 1994-06-24 1999-12-07 Gene Shears Pty., Ltd. Ribozymes with optimized hybridizing arms, stems, and loops, tRNA embedded ribozymes and compositions thereof
US6001988A (en) 1990-06-11 1999-12-14 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands to lectins
US6004925A (en) 1997-09-29 1999-12-21 J. L. Dasseux Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
US6005095A (en) 1995-03-03 1999-12-21 Consiglio Nazionale Delle Ricerche Antisense transcript associated to tumor cells having a T(14;18) translocation and oligodeoxynucleotides useful in the diagnosis and treatment of said tumor cells
US6005013A (en) 1995-08-14 1999-12-21 Massachusetts Institute Of Technology Gear throttle as a nucleation device in a continuous microcellular extrusion system
US6007995A (en) 1998-06-26 1999-12-28 Isis Pharmaceuticals Inc. Antisense inhibition of TNFR1 expression
US6011020A (en) 1990-06-11 2000-01-04 Nexstar Pharmaceuticals, Inc. Nucleic acid ligand complexes
US6011002A (en) 1994-04-08 2000-01-04 The United States Of America As Represented By The Department Of Health And Human Services Circularly permuted ligands and circularly permuted chimeric molecules
US6013522A (en) 1999-02-23 2000-01-11 Isis Pharmaceuticals Inc. Antisense inhibition of human Smad1 expression
US6013443A (en) 1995-05-03 2000-01-11 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: tissue SELEX
US6017756A (en) 1992-05-14 2000-01-25 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting hepatitis B virus replication
US6018042A (en) 1994-08-09 2000-01-25 Novartis Ag Antitumor antisense oligonucleotides
US6020130A (en) 1995-06-07 2000-02-01 Nexstar Pharmaceuticals, Inc. Nucleic acid ligands that bind to and inhibit DNA polymerases
US6019739A (en) 1998-06-18 2000-02-01 Baxter International Inc. Minimally invasive valve annulus sizer
US6025198A (en) 1999-06-25 2000-02-15 Isis Pharmaceuticals Inc. Antisense modulation of Ship-2 expression
US6028186A (en) 1991-06-10 2000-02-22 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of cytokines
US6030776A (en) 1990-06-11 2000-02-29 Nexstar Pharmaceuticals, Inc. Parallel SELEX
US6033910A (en) 1999-07-19 2000-03-07 Isis Pharmaceuticals Inc. Antisense inhibition of MAP kinase kinase 6 expression
US6040147A (en) 1997-04-02 2000-03-21 The Brigham And Women's Hospital, Inc. Systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases and as tools to aid in the selection of agents to be used for the prevention and treatment of atherosclerotic disease
US6040296A (en) 1995-06-07 2000-03-21 East Carolina University Specific antisense oligonucleotide composition & method for treatment of disorders associated with bronchoconstriction and lung inflammation
US6046166A (en) 1997-09-29 2000-04-04 Jean-Louis Dasseux Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
US6046319A (en) 1997-10-22 2000-04-04 University Technologies International, Inc. Antisense oligodeoxynucleotides regulating expression of TNF-α
US6046004A (en) 1997-02-27 2000-04-04 Lorne Park Research, Inc. Solution hybridization of nucleic acids with antisense probes having modified backbones
US6051698A (en) 1997-06-06 2000-04-18 Janjic; Nebojsa Vascular endothelial growth factor (VEGF) nucleic acid ligand complexes
US6057437A (en) 1997-07-25 2000-05-02 Taogosei Co. Ltd. Antisense nucleic acid compounds inhibiting vascular endothelial growth factor
JP2000136202A (en) 1998-10-06 2000-05-16 Commonwealth Biotechnologies Inc Novel heparin binding peptide
US6086918A (en) 1996-03-15 2000-07-11 Unigene Laboratories, Inc. Oral peptide pharmaceutical products
US6090921A (en) 1996-08-23 2000-07-18 Esperion Therapeutics, Inc. Process for purifying apolipoprotein a or apolipoprotein e
US6107457A (en) 1995-02-16 2000-08-22 Board Of Regents, The University Of Texas System Bcr-Abl directed compositions and uses for inhibiting Philadelphia chromosome stimulated cell growth
US6113898A (en) 1995-06-07 2000-09-05 Idec Pharmaceuticals Corporation Human B7.1-specific primatized antibodies and transfectomas expressing said antibodies
US6130364A (en) 1995-03-29 2000-10-10 Abgenix, Inc. Production of antibodies using Cre-mediated site-specific recombination
US6180377B1 (en) 1993-06-16 2001-01-30 Celltech Therapeutics Limited Humanized antibodies
US6191151B1 (en) 1997-11-12 2001-02-20 Howard M. Zik Therapy for herpes neurological viral conditions utilizing 1,4-dihydropyridine calcium channel blockers
US6201165B1 (en) 1997-10-16 2001-03-13 Board Of Regents, University Of Texas System Transgenic animal models for cardiac hypertrophy and methods of use thereof
US6228989B1 (en) 1998-11-13 2001-05-08 The Regents Of The University Of California Peptide substrates phosphorylated by P21-activated protein kinase
AU2673201A (en) 1999-12-20 2001-07-03 Ucb S.A. Alpha-arylethylpiperazine derivatives as neurokinin antagonists
US6287590B1 (en) 1997-10-02 2001-09-11 Esperion Therapeutics, Inc. Peptide/lipid complex formation by co-lyophilization
WO2001075170A1 (en) 2000-03-31 2001-10-11 The Regents Of The University Of California A functional assay of high-density lipoprotein
WO2001075067A2 (en) 2000-03-31 2001-10-11 Hyseq, Inc. Novel nucleic acids and polypeptides
US6303619B1 (en) 1998-03-12 2001-10-16 University Of Virginia Meta-substituted acidic 8-phenylxanthine antagonists of A3 human adenosine receptors
WO2002015923A1 (en) 2000-08-24 2002-02-28 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
EP1186299A1 (en) 2000-09-12 2002-03-13 Universitair Medisch Centrum Utrecht The diagnosis, prevention, and/or succesful treatment of atherosclerosis, infectious diseases, and disturbances in the immune system
US6367479B1 (en) 1995-10-11 2002-04-09 Esperion Luv Development, Inc. Method of forcing the reverse transport of cholesterol from a body part to the liver while avoiding harmful disruptions of hepatic cholesterol homeostasis, and pharmaceutical compositions and kit related thereto
US20020042441A1 (en) 2000-07-25 2002-04-11 Acton John J. N-substituted indoles useful in the treatment of diabetes
US6383808B1 (en) 2000-09-11 2002-05-07 Isis Pharmaceuticals, Inc. Antisense inhibition of clusterin expression
US6410802B1 (en) 1999-04-01 2002-06-25 Esperion Therapeutics, Inc. Methods for synthesizing ether compounds and intermediates therefor
US6423511B1 (en) 1992-09-07 2002-07-23 Kyowa Hakko Kogyo Co., Ltd. Humanized antibodies
US6444681B1 (en) 2000-06-09 2002-09-03 The Ohio State University Research Foundation Methods and compositions for treating Raynaud's Phenomenon and scleroderma
US6444111B1 (en) 1996-07-05 2002-09-03 Combimatrix Corporation Electrochemical solid phase synthesis of polymers
US6444230B1 (en) 1997-04-24 2002-09-03 Chemoxal Sa Synergistic composition of peracetic acid and amine oxide
US20020128175A1 (en) 1998-03-17 2002-09-12 Anantharamaiah Gattadahalli M. Synthetic peptides that enhance atherogenic lipoprotein uptake and lower plasma cholesterol
US20020142369A1 (en) 1999-05-19 2002-10-03 Fersht Alan Roy Refolding method of thrombin
US6464975B2 (en) 1998-12-11 2002-10-15 The Research Foundation Of State University Of New York Compositions and methods for altering cell migration
US6472184B1 (en) 1997-08-22 2002-10-29 Peter Hegemann Method for producing nucleic acid polymers
WO2002098446A1 (en) 2001-06-04 2002-12-12 Nobex Corporation Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same
US6498038B1 (en) 1997-07-15 2002-12-24 Bioprobes, Inc. Loss of sialic acid from apolipoprotein j as an indicator of alcohol intake and/or alcohol related liver damage
US6514523B1 (en) 2000-02-14 2003-02-04 Ottawa Heart Institute Research Corporation Carrier particles for drug delivery and process for preparation
US20030027769A1 (en) 2001-02-16 2003-02-06 Scialdone Mark A. Angiogenesis-inhibitory tripeptides, compositions and their methods of use
US20030040505A1 (en) 2000-03-31 2003-02-27 The Regents Of The University Of California Synthetic phospholipids to ameliorate atherosclerosis and other inflammatory conditions
US20030077641A1 (en) 1998-03-11 2003-04-24 Laskowitz Daniel T. Methods of suppressing microglial activation and systemic inflammatory responses
US6555651B2 (en) 1997-10-09 2003-04-29 The Trustees Of Columbia University In The City Of New York Ligand binding site of rage and uses thereof
US6559284B1 (en) 1996-09-11 2003-05-06 Esperion Therapeutics, Inc. Process for purifying a protein
US20030087819A1 (en) 2001-05-09 2003-05-08 Bielicki John K. Cysteine-containing peptides having antioxidant properties
US20030109442A1 (en) 2001-09-28 2003-06-12 Esperion Therapeutics, Inc. Prevention and treatment of restenosis by local administration of drug
US20030125260A1 (en) 2001-10-31 2003-07-03 Fortuna Haviv Tetra-and pentapeptides having antiangiogenic activity
US6617134B1 (en) 1991-12-13 2003-09-09 Esperion Therapeutics, Inc. Dimer of molecular variant of apolipoprotein and processes for the production thereof
US6635623B1 (en) 1997-06-13 2003-10-21 Baylor College Of Medicine Lipoproteins as nucleic acid vectors
WO2003086326A2 (en) 2002-04-05 2003-10-23 The Regents Of The University Of California G-type peptides to ameliorate atherosclerosis
WO2003089612A2 (en) 2002-04-17 2003-10-30 University Of Florida Research Foundation, Inc. IMPROVED rAAV VECTORS
US20030229015A1 (en) 2000-08-24 2003-12-11 The Regents Of The University Of California Orally administered peptides synergize statin activity
US6673780B2 (en) 2000-10-11 2004-01-06 Esperion Therapeutics, Inc. Sulfoxide and bis-sulfoxide compounds and compositions for cholesterol management and related uses
US6680203B2 (en) 2000-07-10 2004-01-20 Esperion Therapeutics, Inc. Fourier transform mass spectrometry of complex biological samples
US6696545B1 (en) 1997-04-11 2004-02-24 Sangstat Medical Corporation Cytomodulating lipophilic peptides for modulating immune system activity and inhibiting inflammation
US6699910B2 (en) 2000-10-11 2004-03-02 Esperion Therapeutics, Inc. Ketone compounds and compositions for cholesterol management and related uses
US6703422B2 (en) 2000-10-11 2004-03-09 Esperion Therapeutics, Inc. Sulfide and disulfide compounds and compositions for cholesterol management and related uses
US20040059110A1 (en) 2001-02-02 2004-03-25 Ajinomoto Co., Inc. Novel cystine derivative and agent for suppressing activation of inflammatory factors
US6713507B2 (en) 2000-10-11 2004-03-30 Esperion Therapeutics, Inc. Ether compounds and compositions for cholesterol management and related uses
WO2004027027A2 (en) 2002-09-18 2004-04-01 Trustees Of The University Of Pennsylvania Method of inhibiting choroidal neovascularization
US6717031B2 (en) 1995-06-07 2004-04-06 Kate Dora Games Method for selecting a transgenic mouse model of alzheimer's disease
EP1406656A2 (en) 2001-06-08 2004-04-14 Abbott Biotechnology Ltd METHODS OF ADMINISTERING ANTI-TNF$g(a) ANTIBODIES
US6727063B1 (en) 1999-09-10 2004-04-27 Millennium Pharmaceuticals, Inc. Single nucleotide polymorphisms in genes
WO2004034977A2 (en) 2002-10-16 2004-04-29 The Regents Of The University Of California Orally administered peptides synergize statin activity
CA2514303A1 (en) 2002-11-13 2004-05-27 The Uab Research Foundation Synthetic single domain polypeptides mimicking apolipoprotein e and methods of use
WO2004043396A2 (en) 2002-11-09 2004-05-27 Nobex Corporation Modified carbamate-containing prodrugs and methods of synthesizing same
US20040122091A1 (en) 2000-10-11 2004-06-24 Esperion Therapeutics, Inc. Sulfoxide and bis-sulfoxide compounds and compositions for cholesterol management and related uses
US20040136989A1 (en) 2002-07-19 2004-07-15 Abbott Laboratories S.A. Treatment of vasculitides using TNFalpha inhibitors
US20040152623A1 (en) 2002-12-04 2004-08-05 Atul Varadhachary Lactoferrin in the reduction of circulating cholesterol, vascular inflammation, atherosclerosis and cardiovascular disease
US6773719B2 (en) 1994-03-04 2004-08-10 Esperion Luv Development, Inc. Liposomal compositions, and methods of using liposomal compositions to treat dislipidemias
US20040266663A1 (en) 2001-12-07 2004-12-30 Schwartz Daniel M. Methods to increase reverse cholesterol transport in the retinal pigment epithelium (RPE) and bruch's membrane (BM)
US6846636B1 (en) 1998-05-15 2005-01-25 American National Red Cross Methods and compositions for HDL holoparticle uptake receptor
US6849714B1 (en) 1999-05-17 2005-02-01 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
WO2005016280A2 (en) 2003-08-11 2005-02-24 The Regents Of The University Of California Orally administered small peptides synergize statin activity
US6869568B2 (en) 2000-03-31 2005-03-22 The Regents Of The University Of California Functional assay of high-density lipoprotein
US20050070996A1 (en) 2003-04-08 2005-03-31 Dinh Thomas Q. Drug-eluting stent for controlled drug delivery
US6887470B1 (en) 1999-09-10 2005-05-03 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US20050154046A1 (en) 2004-01-12 2005-07-14 Longgui Wang Methods of treating an inflammatory-related disease
US6936691B2 (en) 1999-11-02 2005-08-30 Human Genome Sciences, Inc. Secreted protein HCE3C63
US20050197381A1 (en) 2001-12-13 2005-09-08 Longgui Wang Methods of treating an inflammatory-related disease
US20050239136A1 (en) 2003-12-05 2005-10-27 Hazen Stanley L Risk markers for cardiovacular disease
US6982348B2 (en) 2001-01-26 2006-01-03 Takeda Pharmaceutical Company Limited Aminoethanol derivatives
EP1616572A1 (en) 1998-11-09 2006-01-18 Biogen Idec, Inc. Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-CD20 antibody
WO2006020652A2 (en) 2004-08-11 2006-02-23 The Regents Of The University Of California Orally administered small peptides synergize statin activity
AU2005287004A1 (en) 2004-09-16 2006-03-30 The Regents Of The University Of California G-type peptides and other agents to ameliorate atherosclerosis and other pathologies
US20060069030A1 (en) 2004-07-16 2006-03-30 Trustees Of Tufts College Apolipoprotein A1 mimetics and uses thereof
WO2006063132A2 (en) 2004-12-06 2006-06-15 The Regents Of The University Of California Methods for improving the structure and function of arterioles
US20060172919A1 (en) 2005-02-01 2006-08-03 Hornick Conrad A Inhibition of angiogenesis and destruction of angiogenic vessels by apolipoprotein A-I and high density lipoprotein
US20060217298A1 (en) 2003-02-04 2006-09-28 Srivastava Pramod K Immunogenic cd91 ligand-antigenic molecule complexes and fusion proteins
US20060217307A1 (en) 2001-06-26 2006-09-28 Biomarck Pharmaceuticals, Ltd. Methods for regulating inflammatory mediators and peptides useful therein
WO2006118805A2 (en) 2005-04-29 2006-11-09 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US7144862B2 (en) 2000-08-24 2006-12-05 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US7148199B2 (en) 2003-09-26 2006-12-12 University Of Florida Research Foundation, Inc. Arginyl-glutamine dipeptide for treatment of pathological vascular proliferation
US20070032430A1 (en) 2000-08-24 2007-02-08 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US20070071756A1 (en) 2005-09-26 2007-03-29 Peyman Gholam A Delivery of an agent to ameliorate inflammation
US7291590B2 (en) 2003-06-12 2007-11-06 Queen's University At Kingston Compositions and methods for treating atherosclerosis
WO2008021088A2 (en) 2006-08-08 2008-02-21 The Regents Of The University Of Californina Salicylanilides enhance oral delivery of therapeutic peptides
EP1974747A1 (en) 1998-08-11 2008-10-01 Biogen Idec Inc. Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibody
WO2008143679A2 (en) 2006-06-01 2008-11-27 Verenium Corporation Nucleic acids and proteins and methods for making and using them
US20080293639A1 (en) 2005-04-29 2008-11-27 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
AU2008296478A1 (en) 2007-08-28 2009-03-12 The Uab Research Foundation Synthetic apolipoprotein E mimicking polypeptides and methods of use
WO2009032702A2 (en) 2007-08-28 2009-03-12 Uab Research Foundation Synthetic apolipoprotein e mimicking polypeptides and methods of use
CA2714082A1 (en) 2008-02-07 2009-08-13 Uab Research Foundation Peptides and peptide mimetics to treat pathologies associated with eye disease
US8288335B2 (en) 2004-09-02 2012-10-16 Cognosei, Inc. ApoE analogs and methods for their use
US20130005645A1 (en) 2010-01-06 2013-01-03 Vitek Michael P Apoe peptide dimers and uses thereof
US8568799B2 (en) 2002-03-22 2013-10-29 Unigen, Inc. Isolation of a dual COX-2 and 5-lipoxygenase inhibitor from acacia
WO2014152776A1 (en) 2013-03-14 2014-09-25 Uab Research Foundation Apolipoprotein mimetics and uses thereof
CA2954475A1 (en) 2014-07-31 2016-02-04 Uab Research Foundation Apoe mimetic peptides and higher potency to clear plasma cholesterol
WO2016028665A1 (en) 2014-08-22 2016-02-25 Corning Optical Communications LLC Optical fiber cable with print protective outer surface profile
JP2017505143A (en) 2014-02-10 2017-02-16 アンプテック ゲゼルシャフト ミット ベシュレンクテル ハフツング Incoded RNA

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101568420B (en) * 2006-12-28 2014-06-25 大成普拉斯株式会社 Composite body of metal and resin and manufacturing method thereof

Patent Citations (522)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3687808A (en) 1969-08-14 1972-08-29 Univ Leland Stanford Junior Synthetic polynucleotides
US3767040A (en) 1971-03-01 1973-10-23 Minnesota Mining & Mfg Pressure-sensitive polyurethane adhesives
US4155913A (en) 1973-02-08 1979-05-22 Hoffmann-La Roche Inc. Thienotriazolodiazepine derivatives
US4342566A (en) 1980-02-22 1982-08-03 Scripps Clinic & Research Foundation Solid phase anti-C3 assay for detection of immune complexes
EP0045665A1 (en) 1980-08-06 1982-02-10 Aktiebolaget Hässle Enzyme inhibitors
US4469863A (en) 1980-11-12 1984-09-04 Ts O Paul O P Nonionic nucleic acid alkyl and aryl phosphonates and processes for manufacture and use thereof
US4428938A (en) 1981-06-12 1984-01-31 Richter Gedeon Vegyeszeti Gyar Rt. Peptides affecting the immune regulation and a process for their preparation
US5023243A (en) 1981-10-23 1991-06-11 Molecular Biosystems, Inc. Oligonucleotide therapeutic agent and method of making same
US4476301A (en) 1982-04-29 1984-10-09 Centre National De La Recherche Scientifique Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferon
US4667025A (en) 1982-08-09 1987-05-19 Wakunaga Seiyaku Kabushiki Kaisha Oligonucleotide derivatives
US4789737A (en) 1982-08-09 1988-12-06 Wakunaga Seiyaku Kabushiki Kaisha Oligonucleotide derivatives and production thereof
US4835263A (en) 1983-01-27 1989-05-30 Centre National De La Recherche Scientifique Novel compounds containing an oligonucleotide sequence bonded to an intercalating agent, a process for their synthesis and their use
US4605735A (en) 1983-02-14 1986-08-12 Wakunaga Seiyaku Kabushiki Kaisha Oligonucleotide derivatives
US4948882A (en) 1983-02-22 1990-08-14 Syngene, Inc. Single-stranded labelled oligonucleotides, reactive monomers and methods of synthesis
US5541313A (en) 1983-02-22 1996-07-30 Molecular Biosystems, Inc. Single-stranded labelled oligonucleotides of preselected sequence
US4824941A (en) 1983-03-10 1989-04-25 Julian Gordon Specific antibody to the native form of 2'5'-oligonucleotides, the method of preparation and the use as reagents in immunoassays or for binding 2'5'-oligonucleotides in biological systems
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4587044A (en) 1983-09-01 1986-05-06 The Johns Hopkins University Linkage of proteins to nucleic acids
US5118802A (en) 1983-12-20 1992-06-02 California Institute Of Technology DNA-reporter conjugates linked via the 2' or 5'-primary amino group of the 5'-terminal nucleoside
US5118800A (en) 1983-12-20 1992-06-02 California Institute Of Technology Oligonucleotides possessing a primary amino group in the terminal nucleotide
US4684520A (en) 1984-04-09 1987-08-04 Seuref A.G. Pharmaceutical compositions having cerebral antianoxic and metabolic activities
US4643988A (en) 1984-05-15 1987-02-17 Research Corporation Amphipathic peptides
JPS61126099A (en) 1984-05-15 1986-06-13 リサ−チ・コ−ポレイシヨン Amphoteric ion
US5550111A (en) 1984-07-11 1996-08-27 Temple University-Of The Commonwealth System Of Higher Education Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof
US4981957A (en) 1984-07-19 1991-01-01 Centre National De La Recherche Scientifique Oligonucleotides with modified phosphate and modified carbohydrate moieties at the respective chain termini
US5367066A (en) 1984-10-16 1994-11-22 Chiron Corporation Oligonucleotides with selectably cleavable and/or abasic sites
US5578717A (en) 1984-10-16 1996-11-26 Chiron Corporation Nucleotides for introducing selectably cleavable and/or abasic sites into oligonucleotides
US5258506A (en) 1984-10-16 1993-11-02 Chiron Corporation Photolabile reagents for incorporation into oligonucleotide chains
US5552538A (en) 1984-10-16 1996-09-03 Chiron Corporation Oligonucleotides with cleavable sites
US5545730A (en) 1984-10-16 1996-08-13 Chiron Corporation Multifunctional nucleic acid monomer
US4828979A (en) 1984-11-08 1989-05-09 Life Technologies, Inc. Nucleotide analogs for nucleic acid labeling and detection
US4897355A (en) 1985-01-07 1990-01-30 Syntex (U.S.A.) Inc. N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor
US4845205A (en) 1985-01-08 1989-07-04 Institut Pasteur 2,N6 -disubstituted and 2,N6 -trisubstituted adenosine-3'-phosphoramidites
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5235033A (en) 1985-03-15 1993-08-10 Anti-Gene Development Group Alpha-morpholino ribonucleoside derivatives and polymers thereof
US4762779A (en) 1985-06-13 1988-08-09 Amgen Inc. Compositions and methods for functionalizing nucleic acids
US4980286A (en) 1985-07-05 1990-12-25 Whitehead Institute For Biomedical Research In vivo introduction and expression of foreign genetic material in epithelial cells
US4868116A (en) 1985-07-05 1989-09-19 Whitehead Institute For Biomedical Research Introduction and expression of foreign genetic material in epithelial cells
US5317098A (en) 1986-03-17 1994-05-31 Hiroaki Shizuya Non-radioisotope tagging of fragments
US4877611A (en) 1986-04-15 1989-10-31 Ribi Immunochem Research Inc. Vaccine containing tumor antigens and adjuvants
US4876335A (en) 1986-06-30 1989-10-24 Wakunaga Seiyaku Kabushiki Kaisha Poly-labelled oligonucleotide derivative
US5834185A (en) 1986-10-28 1998-11-10 Johns Hopkins University Formation of triple helix complexes of single stranded nucleic acids using nucleoside oligomers which comprise pyrimidine analogs, triple helix complexes formed thereby and oligomers used in their formation
US5276019A (en) 1987-03-25 1994-01-04 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
US5264423A (en) 1987-03-25 1993-11-23 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
US5286717A (en) 1987-03-25 1994-02-15 The United States Of America As Represented By The Department Of Health And Human Services Inhibitors for replication of retroviruses and for the expression of oncogene products
US4904582A (en) 1987-06-11 1990-02-27 Synthetic Genetics Novel amphiphilic nucleic acid conjugates
US5552540A (en) 1987-06-24 1996-09-03 Howard Florey Institute Of Experimental Physiology And Medicine Nucleoside derivatives
US4946778A (en) 1987-09-21 1990-08-07 Genex Corporation Single polypeptide chain binding molecules
US5585481A (en) 1987-09-21 1996-12-17 Gen-Probe Incorporated Linking reagents for nucleotide probes
US5188897A (en) 1987-10-22 1993-02-23 Temple University Of The Commonwealth System Of Higher Education Encapsulated 2',5'-phosphorothioate oligoadenylates
US5405939A (en) 1987-10-22 1995-04-11 Temple University Of The Commonwealth System Of Higher Education 2',5'-phosphorothioate oligoadenylates and their covalent conjugates with polylysine
US5525465A (en) 1987-10-28 1996-06-11 Howard Florey Institute Of Experimental Physiology And Medicine Oligonucleotide-polyamide conjugates and methods of production and applications of the same
US5112963A (en) 1987-11-12 1992-05-12 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Modified oligonucleotides
US5843708A (en) 1988-01-05 1998-12-01 Ciba-Geigy Corporation Chimeric antibodies
US5082830A (en) 1988-02-26 1992-01-21 Enzo Biochem, Inc. End labeled nucleotide probe
US5519126A (en) 1988-03-25 1996-05-21 University Of Virginia Alumni Patents Foundation Oligonucleotide N-alkylphosphoramidates
US5298490A (en) 1988-05-19 1994-03-29 Immunobiology Research Institute, Inc. Tetra and penta-peptides useful in regulating the immune system
US5453496A (en) 1988-05-26 1995-09-26 University Patents, Inc. Polynucleotide phosphorodithioate
US5278302A (en) 1988-05-26 1994-01-11 University Patents, Inc. Polynucleotide phosphorodithioates
US5109124A (en) 1988-06-01 1992-04-28 Biogen, Inc. Nucleic acid probe linked to a label having a terminal cysteine
US5216141A (en) 1988-06-06 1993-06-01 Benner Steven A Oligonucleotide analogs containing sulfur linkages
US5175273A (en) 1988-07-01 1992-12-29 Genentech, Inc. Nucleic acid intercalating agents
US5294533A (en) 1988-07-05 1994-03-15 Baylor College Of Medicine Antisense oligonucleotide antibiotics complementary to the macromolecular synthesis operon, methods of treating bacterial infections and methods for identification of bacteria
US5262536A (en) 1988-09-15 1993-11-16 E. I. Du Pont De Nemours And Company Reagents for the preparation of 5'-tagged oligonucleotides
US5869339A (en) 1988-09-20 1999-02-09 The Board Of Regents For Northern Illinois University Of Dekalb HIV targeted hairpin ribozymes
US5856188A (en) 1988-09-20 1999-01-05 The Board Of Regents For Northern Illinois University Of Dekalb Hairpin ribozymes
US5866701A (en) 1988-09-20 1999-02-02 The Board Of Regents For Northern Illinois University Of Dekalb HIV targeted hairpin ribozymes
US5512439A (en) 1988-11-21 1996-04-30 Dynal As Oligonucleotide-linked magnetic particles and uses thereof
US5176996A (en) 1988-12-20 1993-01-05 Baylor College Of Medicine Method for making synthetic oligonucleotides which bind specifically to target sites on duplex DNA molecules, by forming a colinear triplex, the synthetic oligonucleotides and methods of use
US5599923A (en) 1989-03-06 1997-02-04 Board Of Regents, University Of Tx Texaphyrin metal complexes having improved functionalization
US5168053A (en) 1989-03-24 1992-12-01 Yale University Cleavage of targeted RNA by RNAase P
US5728521A (en) 1989-03-24 1998-03-17 Yale University Targeted cleavage of RNA using eukaryotic ribonuclease P and external guide sequence
US5624824A (en) 1989-03-24 1997-04-29 Yale University Targeted cleavage of RNA using eukaryotic ribonuclease P and external guide sequence
US5391723A (en) 1989-05-31 1995-02-21 Neorx Corporation Oligonucleotide conjugates
US5416203A (en) 1989-06-06 1995-05-16 Northwestern University Steroid modified oligonucleotides
US4958013A (en) 1989-06-06 1990-09-18 Northwestern University Cholesteryl modified oligonucleotides
US5473039A (en) 1989-08-18 1995-12-05 The Scripps Research Institute Polypeptide analogs of apolipoprotein E, diagnostic systems and methods using the analogs
US5451463A (en) 1989-08-28 1995-09-19 Clontech Laboratories, Inc. Non-nucleoside 1,3-diol reagents for labeling synthetic oligonucleotides
US5134066A (en) 1989-08-29 1992-07-28 Monsanto Company Improved probes using nucleosides containing 3-dezauracil analogs
US5770576A (en) 1989-08-30 1998-06-23 Cytran, Inc. Pharmaceutical dipeptide compositions and methods of use thereof: systemic toxicity
US5254469A (en) 1989-09-12 1993-10-19 Eastman Kodak Company Oligonucleotide-enzyme conjugate that can be used as a probe in hybridization assays and polymerase chain reaction procedures
US5591722A (en) 1989-09-15 1997-01-07 Southern Research Institute 2'-deoxy-4'-thioribonucleosides and their antiviral activity
US5399676A (en) 1989-10-23 1995-03-21 Gilead Sciences Oligonucleotides with inverted polarity
US5466786B1 (en) 1989-10-24 1998-04-07 Gilead Sciences 2' Modified nucleoside and nucleotide compounds
US5466786A (en) 1989-10-24 1995-11-14 Gilead Sciences 2'modified nucleoside and nucleotide compounds
US5264564A (en) 1989-10-24 1993-11-23 Gilead Sciences Oligonucleotide analogs with novel linkages
US5264562A (en) 1989-10-24 1993-11-23 Gilead Sciences, Inc. Oligonucleotide analogs with novel linkages
US5292873A (en) 1989-11-29 1994-03-08 The Research Foundation Of State University Of New York Nucleic acids labeled with naphthoquinone probe
US5455233A (en) 1989-11-30 1995-10-03 University Of North Carolina Oligoribonucleoside and oligodeoxyribonucleoside boranophosphates
US5436330A (en) 1989-12-19 1995-07-25 Agency Of Industrial Science & Technology Hammerhead ribozymes with enhanced stability provided by an additional 3' ha
US5405938A (en) 1989-12-20 1995-04-11 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5130302A (en) 1989-12-20 1992-07-14 Boron Bilogicals, Inc. Boronated nucleoside, nucleotide and oligonucleotide compounds, compositions and methods for using same
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5486603A (en) 1990-01-08 1996-01-23 Gilead Sciences, Inc. Oligonucleotide having enhanced binding affinity
US5480869A (en) 1990-01-09 1996-01-02 The Regents Of The University Of California Anti-inflammatory peptide analogs and treatment to inhibit vascular leakage in injured tissues
US5681941A (en) 1990-01-11 1997-10-28 Isis Pharmaceuticals, Inc. Substituted purines and oligonucleotide cross-linking
US5670633A (en) 1990-01-11 1997-09-23 Isis Pharmaceuticals, Inc. Sugar modified oligonucleotides that detect and modulate gene expression
US5646265A (en) 1990-01-11 1997-07-08 Isis Pharmceuticals, Inc. Process for the preparation of 2'-O-alkyl purine phosphoramidites
US5459255A (en) 1990-01-11 1995-10-17 Isis Pharmaceuticals, Inc. N-2 substituted purines
US5578718A (en) 1990-01-11 1996-11-26 Isis Pharmaceuticals, Inc. Thiol-derivatized nucleosides
US5587469A (en) 1990-01-11 1996-12-24 Isis Pharmaceuticals, Inc. Oligonucleotides containing N-2 substituted purines
US5939598A (en) 1990-01-12 1999-08-17 Abgenix, Inc. Method of making transgenic mice lacking endogenous heavy chains
US5214136A (en) 1990-02-20 1993-05-25 Gilead Sciences, Inc. Anthraquinone-derivatives oligonucleotides
US5414077A (en) 1990-02-20 1995-05-09 Gilead Sciences Non-nucleoside linkers for convenient attachment of labels to oligonucleotides using standard synthetic methods
US5541306A (en) 1990-03-08 1996-07-30 Worcester Foundation For Biomedical Research Aminoalkylphosphotriester oligonucleotide derivatives
US5563253A (en) 1990-03-08 1996-10-08 Worcester Foundation For Biomedical Research Linear aminoalkylphosphoramidate oligonucleotide derivatives
US5321131A (en) 1990-03-08 1994-06-14 Hybridon, Inc. Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling
US5536821A (en) 1990-03-08 1996-07-16 Worcester Foundation For Biomedical Research Aminoalkylphosphorothioamidate oligonucleotide deratives
US5470967A (en) 1990-04-10 1995-11-28 The Dupont Merck Pharmaceutical Company Oligonucleotide analogs with sulfamate linkages
US5567811A (en) 1990-05-03 1996-10-22 Amersham International Plc Phosphoramidite derivatives, their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides
US5514785A (en) 1990-05-11 1996-05-07 Becton Dickinson And Company Solid supports for nucleic acid hybridization assays
US5814467A (en) 1990-06-07 1998-09-29 The Scripps Research Institute APO AI polypeptides, diagnostic methods and systems for quantifying APO AI, and therapeutic methods
US5864026A (en) 1990-06-11 1999-01-26 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: tissue selex
US5795721A (en) 1990-06-11 1998-08-18 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of ICP4
US5846713A (en) 1990-06-11 1998-12-08 Nexstar Pharmaceuticals, Inc. High affinity HKGF nucleic acid ligands and inhibitors
US5731424A (en) 1990-06-11 1998-03-24 Nexstar Pharmaceuticals, Inc. High affinity TGFβ nucleic acid ligands and inhibitors
US6011020A (en) 1990-06-11 2000-01-04 Nexstar Pharmaceuticals, Inc. Nucleic acid ligand complexes
US5869641A (en) 1990-06-11 1999-02-09 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of CD4
US5958691A (en) 1990-06-11 1999-09-28 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands containing modified nucleotides
US6001988A (en) 1990-06-11 1999-12-14 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands to lectins
US5580737A (en) 1990-06-11 1996-12-03 Nexstar Pharmaceuticals, Inc. High-affinity nucleic acid ligands that discriminate between theophylline and caffeine
US5503978A (en) 1990-06-11 1996-04-02 University Research Corporation Method for identification of high affinity DNA ligands of HIV-1 reverse transcriptase
US5476766A (en) 1990-06-11 1995-12-19 Nexstar Pharmaceuticals, Inc. Ligands of thrombin
US5543293A (en) 1990-06-11 1996-08-06 Nexstar Pharmaceuticals, Inc. DNA ligands of thrombin
US6030776A (en) 1990-06-11 2000-02-29 Nexstar Pharmaceuticals, Inc. Parallel SELEX
US5786462A (en) 1990-06-11 1998-07-28 Nexstar Pharmaceuticals, Inc. High affinity ssDNA ligands of HIV-1 reverse transcriptase
US5780228A (en) 1990-06-11 1998-07-14 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands to lectins
US5135917A (en) 1990-07-12 1992-08-04 Nova Pharmaceutical Corporation Interleukin receptor expression inhibiting antisense oligonucleotides
US5541307A (en) 1990-07-27 1996-07-30 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogs and solid phase synthesis thereof
US5614617A (en) 1990-07-27 1997-03-25 Isis Pharmaceuticals, Inc. Nuclease resistant, pyrimidine modified oligonucleotides that detect and modulate gene expression
US5218105A (en) 1990-07-27 1993-06-08 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5608046A (en) 1990-07-27 1997-03-04 Isis Pharmaceuticals, Inc. Conjugated 4'-desmethyl nucleoside analog compounds
US5623070A (en) 1990-07-27 1997-04-22 Isis Pharmaceuticals, Inc. Heteroatomic oligonucleoside linkages
US5610289A (en) 1990-07-27 1997-03-11 Isis Pharmaceuticals, Inc. Backbone modified oligonucleotide analogues
US5602240A (en) 1990-07-27 1997-02-11 Ciba Geigy Ag. Backbone modified oligonucleotide analogs
US5677437A (en) 1990-07-27 1997-10-14 Isis Pharmaceuticals, Inc. Heteroatomic oligonucleoside linkages
US5618704A (en) 1990-07-27 1997-04-08 Isis Pharmacueticals, Inc. Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling
US5138045A (en) 1990-07-27 1992-08-11 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5688941A (en) 1990-07-27 1997-11-18 Isis Pharmaceuticals, Inc. Methods of making conjugated 4' desmethyl nucleoside analog compounds
US5489677A (en) 1990-07-27 1996-02-06 Isis Pharmaceuticals, Inc. Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms
US5677439A (en) 1990-08-03 1997-10-14 Sanofi Oligonucleotide analogues containing phosphate diester linkage substitutes, compositions thereof, and precursor dinucleotide analogues
US5245022A (en) 1990-08-03 1993-09-14 Sterling Drug, Inc. Exonuclease resistant terminally substituted oligonucleotides
US5567810A (en) 1990-08-03 1996-10-22 Sterling Drug, Inc. Nuclease resistant compounds
US5177196A (en) 1990-08-16 1993-01-05 Microprobe Corporation Oligo (α-arabinofuranosyl nucleotides) and α-arabinofuranosyl precursors thereof
US5512667A (en) 1990-08-28 1996-04-30 Reed; Michael W. Trifunctional intermediates for preparing 3'-tailed oligonucleotides
US5721367A (en) 1990-08-29 1998-02-24 Pharming B.V. Homologous recombination in mammalian cells
US5214134A (en) 1990-09-12 1993-05-25 Sterling Winthrop Inc. Process of linking nucleosides with a siloxane bridge
US5561225A (en) 1990-09-19 1996-10-01 Southern Research Institute Polynucleotide analogs containing sulfonate and sulfonamide internucleoside linkages
US5596086A (en) 1990-09-20 1997-01-21 Gilead Sciences, Inc. Modified internucleoside linkages having one nitrogen and two carbon atoms
US5432272A (en) 1990-10-09 1995-07-11 Benner; Steven A. Method for incorporating into a DNA or RNA oligonucleotide using nucleotides bearing heterocyclic bases
US5391377A (en) 1990-10-19 1995-02-21 Cortecs Limited Biphasic release formations for lipophilic acids
US5691317A (en) 1990-11-02 1997-11-25 Cho-Chung; Yoon S. Antisense oligonucleotides of human regulatory subunit RI-alpha of cAMP dependent protein kinases for the treatment of cancer
US5627158A (en) 1990-11-02 1997-05-06 Cho-Chung; Yoon S. Antisense oligonucleotides of human regulatory subunit RI-.sub.α of camp dependent protein kinases for the treatment of cancer
US5510475A (en) 1990-11-08 1996-04-23 Hybridon, Inc. Oligonucleotide multiple reporter precursors
US5612895A (en) 1990-12-14 1997-03-18 Balaji; Vitukudi N. Method of rational drug design based on ab initio computer simulation of conformational features of peptides
US5579250A (en) 1990-12-14 1996-11-26 Balaji; Vitukudi N. Method of rational drug design based on AB initio computer simulation of conformational features of peptides
US5683874A (en) 1991-03-27 1997-11-04 Research Corporation Technologies, Inc. Single-stranded circular oligonucleotides capable of forming a triplex with a target sequence
US5714331A (en) 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
US6028186A (en) 1991-06-10 2000-02-22 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands of cytokines
US5334711A (en) 1991-06-20 1994-08-02 Europaisches Laboratorium Fur Molekularbiologie (Embl) Synthetic catalytic oligonucleotide structures
US5371241A (en) 1991-07-19 1994-12-06 Pharmacia P-L Biochemicals Inc. Fluorescein labelled phosphoramidites
US5571799A (en) 1991-08-12 1996-11-05 Basco, Ltd. (2'-5') oligoadenylate analogues useful as inhibitors of host-v5.-graft response
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
US5587361A (en) 1991-10-15 1996-12-24 Isis Pharmaceuticals, Inc. Oligonucleotides having phosphorothioate linkages of high chiral purity
US5319080A (en) 1991-10-17 1994-06-07 Ciba-Geigy Corporation Bicyclic nucleosides, oligonucleotides, process for their preparation and intermediates
US5393878A (en) 1991-10-17 1995-02-28 Ciba-Geigy Corporation Bicyclic nucleosides, oligonucleotides, process for their preparation and intermediates
US5594121A (en) 1991-11-07 1997-01-14 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified purines
US5645985A (en) 1991-11-26 1997-07-08 Gilead Sciences, Inc. Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines
US5484908A (en) 1991-11-26 1996-01-16 Gilead Sciences, Inc. Oligonucleotides containing 5-propynyl pyrimidines
US5359044A (en) 1991-12-13 1994-10-25 Isis Pharmaceuticals Cyclobutyl oligonucleotide surrogates
US6617134B1 (en) 1991-12-13 2003-09-09 Esperion Therapeutics, Inc. Dimer of molecular variant of apolipoprotein and processes for the production thereof
US5700922A (en) 1991-12-24 1997-12-23 Isis Pharmaceuticals, Inc. PNA-DNA-PNA chimeric macromolecules
US5565552A (en) 1992-01-21 1996-10-15 Pharmacyclics, Inc. Method of expanded porphyrin-oligonucleotide conjugate synthesis
US5587371A (en) 1992-01-21 1996-12-24 Pharmacyclics, Inc. Texaphyrin-oligonucleotide conjugates
US5595726A (en) 1992-01-21 1997-01-21 Pharmacyclics, Inc. Chromophore probe for detection of nucleic acid
US5652094A (en) 1992-01-31 1997-07-29 University Of Montreal Nucleozymes
US5639873A (en) 1992-02-05 1997-06-17 Centre National De La Recherche Scientifique (Cnrs) Oligothionucleotides
US5633360A (en) 1992-04-14 1997-05-27 Gilead Sciences, Inc. Oligonucleotide analogs capable of passive cell membrane permeation
US5457135A (en) 1992-05-08 1995-10-10 Baranowitz; Steven Treatment of age related macular degeneration with beta-carotene
US5646020A (en) 1992-05-14 1997-07-08 Ribozyme Pharmaceuticals, Inc. Hammerhead ribozymes for preferred targets
US5972699A (en) 1992-05-14 1999-10-26 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting herpes simplex virus replication
US5693535A (en) 1992-05-14 1997-12-02 Ribozyme Pharmaceuticals, Inc. HIV targeted ribozymes
US6017756A (en) 1992-05-14 2000-01-25 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting hepatitis B virus replication
US5972704A (en) 1992-05-14 1999-10-26 Ribozyme Pharmaceuticals, Inc. HIV nef targeted ribozymes
US5989906A (en) 1992-05-14 1999-11-23 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting P-glycoprotein (mdr-1-gene)
US5869253A (en) 1992-05-14 1999-02-09 Ribozyme Pharmaceuticals, Inc. Method and reagent for inhibiting hepatitis C virus replication
US5434257A (en) 1992-06-01 1995-07-18 Gilead Sciences, Inc. Binding compentent oligomers containing unsaturated 3',5' and 2',5' linkages
JPH07507554A (en) 1992-06-12 1995-08-24 エヌ・ブイ・イノゲネテイクス・エス・エイ Novel peptides and proteins, methods of their preparation, and their use as cholesterol receptors
WO1993025581A1 (en) 1992-06-12 1993-12-23 N.V. Innogenetics S.A. New peptides and proteins, process for their preparation and their use as cholesterol acceptors
US5733879A (en) 1992-06-12 1998-03-31 N.V. Innogenetics, S.A. Peptides and proteins, process for their preparation and their use as cholesterol acceptors
US5700920A (en) 1992-07-01 1997-12-23 Novartis Corporation Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use and intermediates
US5610300A (en) 1992-07-01 1997-03-11 Ciba-Geigy Corporation Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use and intermediates
US5631115A (en) 1992-07-02 1997-05-20 Sankyo Company, Limited Looped, hairpin ribozyme
US5272250A (en) 1992-07-10 1993-12-21 Spielvogel Bernard F Boronated phosphoramidate compounds
US5344822A (en) 1992-08-12 1994-09-06 The Rogosin Institute Methods useful in endotoxin prophylaxis and therapy
US5733549A (en) 1992-08-14 1998-03-31 Shino-Test Corporation Peptides including amino acid sequences selected from lipoprotein (a) and apolipoprotein (a), antibodies recognizing these amino acid sequences, and methods of determination using these antibodies
US5646042A (en) 1992-08-26 1997-07-08 Ribozyme Pharmaceuticals, Inc. C-myb targeted ribozymes
US6423511B1 (en) 1992-09-07 2002-07-23 Kyowa Hakko Kogyo Co., Ltd. Humanized antibodies
US5804440A (en) 1992-09-30 1998-09-08 The Scripps Research Institute Human neutralizing monoclonal antibodies to human immunodeficiency virus
US5891684A (en) 1992-10-15 1999-04-06 Ribozyme Pharmaceuticals, Inc. Base-modified enzymatic nucleic acid
US5811300A (en) 1992-12-07 1998-09-22 Ribozyme Pharmaceuticals, Inc. TNF-α ribozymes
US5731295A (en) 1992-12-07 1998-03-24 Ribozyme Pharmaceuticals, Inc. Method of reducing stromelysin RNA via ribozymes
US5358934A (en) 1992-12-11 1994-10-25 The United States Of America As Represented By The Secretary Of Agriculture Materials and methods for control of pests
US5721138A (en) 1992-12-15 1998-02-24 Sandford University Apolipoprotein(A) promoter and regulatory sequence constructs and methods of use
US5574142A (en) 1992-12-15 1996-11-12 Microprobe Corporation Peptide linkers for improved oligonucleotide delivery
US5652107A (en) 1993-01-15 1997-07-29 The Public Health Research Institute Of The City Of New York, Inc. Diagnostic assays and kits for RNA using RNA binary probes and a ribozyme ligase
US5786138A (en) 1993-01-29 1998-07-28 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Hyperstabilizing antisense nucleic acid binding agents
US5476925A (en) 1993-02-01 1995-12-19 Northwestern University Oligodeoxyribonucleotides including 3'-aminonucleoside-phosphoramidate linkages and terminal 3'-amino groups
US5508060A (en) 1993-02-11 1996-04-16 Minnesota Mining And Manufacturing Company Method of polymer impregnation
US5466677A (en) 1993-03-06 1995-11-14 Ciba-Geigy Corporation Dinucleoside phosphinates and their pharmaceutical compositions
US5576427A (en) 1993-03-30 1996-11-19 Sterling Winthrop, Inc. Acyclic nucleoside analogs and oligonucleotide sequences containing them
US5663312A (en) 1993-03-31 1997-09-02 Sanofi Oligonucleotide dimers with amide linkages replacing phosphodiester linkages
US5658873A (en) 1993-04-10 1997-08-19 Degussa Aktiengesellschaft Coated sodium percarbonate particles, a process for their production and detergent, cleaning and bleaching compositions containing them
US5539082A (en) 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5990088A (en) 1993-06-04 1999-11-23 The United States Of America As Represented By The Department Of Health And Human Services Method for treating kaposi's sarcoma with antisense oligonucleotides
US6180377B1 (en) 1993-06-16 2001-01-30 Celltech Therapeutics Limited Humanized antibodies
US5962426A (en) 1993-06-25 1999-10-05 Yale University Triple-helix forming oligonucleotides for targeted mutagenesis
US5891683A (en) 1993-09-02 1999-04-06 Ribozyme Pharmaceuticals, Inc. Non-nucleotide containing enzymatic nucleic acid
US5502177A (en) 1993-09-17 1996-03-26 Gilead Sciences, Inc. Pyrimidine derivatives for labeled binding partners
EP0643965A1 (en) 1993-09-20 1995-03-22 Kos Pharmaceuticals, Inc. Nicotinic acid compositions for treating hyperlipidemia
US5861288A (en) 1993-10-18 1999-01-19 Ribozyme Pharmaceuticals, Inc. Catalytic DNA
US5616466A (en) 1993-11-05 1997-04-01 Cantor; Glenn H. Ribozyme-mediated inhibition of bovine leukemia virus
US5719262A (en) 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
US5919772A (en) 1993-12-01 1999-07-06 Mcgill University Antisense oligonucleotides having tumorigenicity-inhibiting activity
US5457187A (en) 1993-12-08 1995-10-10 Board Of Regents University Of Nebraska Oligonucleotides containing 5-fluorouracil
US5446137A (en) 1993-12-09 1995-08-29 Syntex (U.S.A.) Inc. Oligonucleotides containing 4'-substituted nucleotides
US5446137B1 (en) 1993-12-09 1998-10-06 Behringwerke Ag Oligonucleotides containing 4'-substituted nucleotides
US5712384A (en) 1994-01-05 1998-01-27 Gene Shears Pty Ltd. Ribozymes targeting retroviral packaging sequence expression constructs and recombinant retroviruses containing such constructs
US5641754A (en) 1994-01-10 1997-06-24 The Board Of Regents Of The University Of Nebraska Antisense oligonucleotide compositions for selectively killing cancer cells
US5519134A (en) 1994-01-11 1996-05-21 Isis Pharmaceuticals, Inc. Pyrrolidine-containing monomers and oligomers
US5599928A (en) 1994-02-15 1997-02-04 Pharmacyclics, Inc. Texaphyrin compounds having improved functionalization
US6773719B2 (en) 1994-03-04 2004-08-10 Esperion Luv Development, Inc. Liposomal compositions, and methods of using liposomal compositions to treat dislipidemias
US20040224011A1 (en) 1994-03-04 2004-11-11 The University Of British Columbia Liposomal compositions and methods of using the same to treat dyslipidemias
US5869248A (en) 1994-03-07 1999-02-09 Yale University Targeted cleavage of RNA using ribonuclease P targeting and cleavage sequences
US5596091A (en) 1994-03-18 1997-01-21 The Regents Of The University Of California Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides
US5627053A (en) 1994-03-29 1997-05-06 Ribozyme Pharmaceuticals, Inc. 2'deoxy-2'-alkylnucleotide containing nucleic acid
US5985621A (en) 1994-03-29 1999-11-16 Ribozyme Pharmaceuticals, Inc. 2'-deoxy-2'-alkylnucleotide containing nucleic acid
US5625050A (en) 1994-03-31 1997-04-29 Amgen Inc. Modified oligonucleotides and intermediates useful in nucleic acid therapeutics
US6011002A (en) 1994-04-08 2000-01-04 The United States Of America As Represented By The Department Of Health And Human Services Circularly permuted ligands and circularly permuted chimeric molecules
US5683902A (en) 1994-05-13 1997-11-04 Northern Illinois University Human papilloma virus inhibition by a hairpin ribozyme
US5580967A (en) 1994-05-13 1996-12-03 The Scripps Research Institute Optimized catalytic DNA-cleaving ribozymes
US5595873A (en) 1994-05-13 1997-01-21 The Scripps Research Institute T. thermophila group I introns that cleave amide bonds
US5525711A (en) 1994-05-18 1996-06-11 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Pteridine nucleotide analogs as fluorescent DNA probes
US5650316A (en) 1994-06-06 1997-07-22 Research Development Foundation Uses of triplex forming oligonucleotides for the treatment of human diseases
US5998193A (en) 1994-06-24 1999-12-07 Gene Shears Pty., Ltd. Ribozymes with optimized hybridizing arms, stems, and loops, tRNA embedded ribozymes and compositions thereof
US5633133A (en) 1994-07-14 1997-05-27 Long; David M. Ligation with hammerhead ribozymes
US5597696A (en) 1994-07-18 1997-01-28 Becton Dickinson And Company Covalent cyanine dye oligonucleotide conjugates
US6018042A (en) 1994-08-09 2000-01-25 Novartis Ag Antitumor antisense oligonucleotides
US5591584A (en) 1994-08-25 1997-01-07 Chiron Corporation N-4 modified pyrimidine deoxynucleotides and oligonucleotide probes synthesized therewith
US5580731A (en) 1994-08-25 1996-12-03 Chiron Corporation N-4 modified pyrimidine deoxynucleotides and oligonucleotide probes synthesized therewith
US5597909A (en) 1994-08-25 1997-01-28 Chiron Corporation Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use
US5688670A (en) 1994-09-01 1997-11-18 The General Hospital Corporation Self-modifying RNA molecules and methods of making
US5595973A (en) 1994-09-12 1997-01-21 Biomeasure Incorporated Protection of hemopoietic cells during chemotherapy or radiotherapy
US5989908A (en) 1994-09-12 1999-11-23 City Of Hope Modulation of drug and radiation resistant genes
US5858660A (en) 1994-09-20 1999-01-12 Nexstar Pharmaceuticlas, Inc. Parallel selex
US5877022A (en) 1994-09-23 1999-03-02 Ribozyme Pharmaceuticals, Inc Ribozymes targeted to APO(a) RNA
US5856103A (en) 1994-10-07 1999-01-05 Board Of Regents The University Of Texas Method for selectively ranking sequences for antisense targeting
US5837855A (en) 1994-10-11 1998-11-17 Ribozyme Pharmaceutical, Inc. Hairpin ribozymes
US6022962A (en) 1994-10-11 2000-02-08 Ribozyme Pharmaceutical, Inc. Hairpin ribozymes
US5869246A (en) 1994-10-14 1999-02-09 Taiho Pharmaceutical Co., Ltd. Triplex Oligonucleotides targeted to p120
US5807718A (en) 1994-12-02 1998-09-15 The Scripps Research Institute Enzymatic DNA molecules
US5683873A (en) 1995-01-13 1997-11-04 Innovir Laboratories, Inc. EGS-mediated inactivation of target RNA
US5631146A (en) 1995-01-19 1997-05-20 The General Hospital Corporation DNA aptamers and catalysts that bind adenosine or adenosine-5'-phosphates and methods for isolation thereof
US5994320A (en) 1995-02-06 1999-11-30 Regents Of The University Of Minnesota Antisense oligonucleotides and methods for treating central nervous system tumors
US6107457A (en) 1995-02-16 2000-08-22 Board Of Regents, The University Of Texas System Bcr-Abl directed compositions and uses for inhibiting Philadelphia chromosome stimulated cell growth
US6005095A (en) 1995-03-03 1999-12-21 Consiglio Nazionale Delle Ricerche Antisense transcript associated to tumor cells having a T(14;18) translocation and oligodeoxynucleotides useful in the diagnosis and treatment of said tumor cells
US6506879B1 (en) 1995-03-03 2003-01-14 Esperion Therapeutics, Inc. Purified Apo A and Apo E compounds and methods for using them
US5990081A (en) 1995-03-03 1999-11-23 Esperion Therapeutics, Inc. Purified APO A and APO E compounds and methods for using them
US5770715A (en) 1995-03-22 1998-06-23 Toagosei Co., Ltd. Hammerhead-like nucleic acid analogues and their synthesis
US6130364A (en) 1995-03-29 2000-10-10 Abgenix, Inc. Production of antibodies using Cre-mediated site-specific recombination
US5631280A (en) 1995-03-29 1997-05-20 Merck & Co., Inc. Inhibitors of farnesyl-protein transferase
US6458592B1 (en) 1995-03-29 2002-10-01 Abgenix, Inc. Production of antibodies using cre-mediated site-specific recombination
US6013443A (en) 1995-05-03 2000-01-11 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: tissue SELEX
US5646031A (en) 1995-05-16 1997-07-08 Northern Illinois University SArMV and sCYMVI hairpin ribozymes
US5910408A (en) 1995-06-07 1999-06-08 The General Hospital Corporation Catalytic DNA having ligase activity
US6040296A (en) 1995-06-07 2000-03-21 East Carolina University Specific antisense oligonucleotide composition & method for treatment of disorders associated with bronchoconstriction and lung inflammation
US5693773A (en) 1995-06-07 1997-12-02 Hybridon Incorporated Triplex-forming antisense oligonucleotides having abasic linkers targeting nucleic acids comprising mixed sequences of purines and pyrimidines
US6717031B2 (en) 1995-06-07 2004-04-06 Kate Dora Games Method for selecting a transgenic mouse model of alzheimer's disease
US6020130A (en) 1995-06-07 2000-02-01 Nexstar Pharmaceuticals, Inc. Nucleic acid ligands that bind to and inhibit DNA polymerases
US5837243A (en) 1995-06-07 1998-11-17 Medarex, Inc. Therapeutic compounds comprised of anti-Fc receptor antibodies
US6113898A (en) 1995-06-07 2000-09-05 Idec Pharmaceuticals Corporation Human B7.1-specific primatized antibodies and transfectomas expressing said antibodies
US5877021A (en) 1995-07-07 1999-03-02 Ribozyme Pharmaceuticals, Inc. B7-1 targeted ribozymes
US6005013A (en) 1995-08-14 1999-12-21 Massachusetts Institute Of Technology Gear throttle as a nucleation device in a continuous microcellular extrusion system
US5854238A (en) 1995-09-09 1998-12-29 Hoffmann-La Roche Inc. Use of a thienotriazolodiazephine to increase apolipoprotein A-I levels
US5856463A (en) 1995-09-18 1999-01-05 Prydz; Hans Peter Blankenborg PSKH-1 ribozymes
US20020071862A1 (en) 1995-10-11 2002-06-13 Esperion Luv Development, Inc. Method of forcing the reverse transport of cholesterol from a body part to the liver while avoiding harmful disruptions of hepatic cholesterol homeostasis, and pharmaceutical compositions, and kit related thereto
US6367479B1 (en) 1995-10-11 2002-04-09 Esperion Luv Development, Inc. Method of forcing the reverse transport of cholesterol from a body part to the liver while avoiding harmful disruptions of hepatic cholesterol homeostasis, and pharmaceutical compositions and kit related thereto
US5780607A (en) 1995-10-13 1998-07-14 Hoffmann-La Roche Inc. Antisense oligomers
US6017898A (en) 1995-11-21 2000-01-25 Icn Pharmaceuticals, Inc. Inhibition of tumor growth by antisense oligonucleotides for IL-8 and IL-8 receptor
US5849903A (en) 1995-11-21 1998-12-15 Icn Pharmaceuticals, Inc. Antisense oligonucleotides for IL-8 and IL-8 receptor
US5998602A (en) 1996-02-15 1999-12-07 The Cleveland Clinic Fouindation And Government RNase L activators and antisense oligonucleotides effective to treat RSV infections
US5877162A (en) 1996-03-14 1999-03-02 Innovir Laboratories, Inc. Short external guide sequences
US6086918A (en) 1996-03-15 2000-07-11 Unigene Laboratories, Inc. Oral peptide pharmaceutical products
WO1997036927A1 (en) 1996-03-29 1997-10-09 Dario Boffelli Amphipathic molecules as cholesterol and other lipid uptake inhibitors
US20010005714A1 (en) 1996-03-29 2001-06-28 Dario Boffelli Amphipathic molecules as cholesterol and other lipid uptake inhibitors
US5998203A (en) 1996-04-16 1999-12-07 Ribozyme Pharmaceuticals, Inc. Enzymatic nucleic acids containing 5'-and/or 3'-cap structures
US5877153A (en) 1996-06-11 1999-03-02 Commonwealth Biotechnologies Inc. Heparin-binding peptides
US5792613A (en) 1996-06-12 1998-08-11 The Curators Of The University Of Missouri Method for obtaining RNA aptamers based on shape selection
US6444111B1 (en) 1996-07-05 2002-09-03 Combimatrix Corporation Electrochemical solid phase synthesis of polymers
US5955590A (en) 1996-07-15 1999-09-21 Worcester Foundation For Biomedical Research Conjugates of minor groove DNA binders with antisense oligonucleotides
US6423830B1 (en) 1996-08-23 2002-07-23 Esperion Therapeutics, Inc. Process for purifying apolipoprotein A or apolipoprotein E
US6090921A (en) 1996-08-23 2000-07-18 Esperion Therapeutics, Inc. Process for purifying apolipoprotein a or apolipoprotein e
US6156727A (en) 1996-09-05 2000-12-05 Uab Research Foundation Anti-atherosclerotic peptides and a transgenic mouse model of antherosclerosis
WO1998009602A2 (en) 1996-09-05 1998-03-12 The Uab Research Foundation Anti-atherosclerotic peptides and a transgenic mouse model of atherosclerosis
US6559284B1 (en) 1996-09-11 2003-05-06 Esperion Therapeutics, Inc. Process for purifying a protein
US5874566A (en) 1996-10-25 1999-02-23 Hisamitsu Pharmaceutical Co. Inc. Il-15 triplex oligonucleotides
US5861254A (en) 1997-01-31 1999-01-19 Nexstar Pharmaceuticals, Inc. Flow cell SELEX
US6046004A (en) 1997-02-27 2000-04-04 Lorne Park Research, Inc. Solution hybridization of nucleic acids with antisense probes having modified backbones
US6040147A (en) 1997-04-02 2000-03-21 The Brigham And Women's Hospital, Inc. Systemic inflammatory markers as diagnostic tools in the prevention of atherosclerotic diseases and as tools to aid in the selection of agents to be used for the prevention and treatment of atherosclerotic disease
US6696545B1 (en) 1997-04-11 2004-02-24 Sangstat Medical Corporation Cytomodulating lipophilic peptides for modulating immune system activity and inhibiting inflammation
US6444230B1 (en) 1997-04-24 2002-09-03 Chemoxal Sa Synergistic composition of peracetic acid and amine oxide
US6051698A (en) 1997-06-06 2000-04-18 Janjic; Nebojsa Vascular endothelial growth factor (VEGF) nucleic acid ligand complexes
US6635623B1 (en) 1997-06-13 2003-10-21 Baylor College Of Medicine Lipoproteins as nucleic acid vectors
US6498038B1 (en) 1997-07-15 2002-12-24 Bioprobes, Inc. Loss of sialic acid from apolipoprotein j as an indicator of alcohol intake and/or alcohol related liver damage
US6057437A (en) 1997-07-25 2000-05-02 Taogosei Co. Ltd. Antisense nucleic acid compounds inhibiting vascular endothelial growth factor
US6472184B1 (en) 1997-08-22 2002-10-29 Peter Hegemann Method for producing nucleic acid polymers
US5800758A (en) 1997-09-16 1998-09-01 Kimberly-Clark Worldwide, Inc. Process for making microporous films with improved properties
US7312190B2 (en) 1997-09-29 2007-12-25 Jean-Louis Dasseux Pharmaceutical compositions of apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
WO1999016409A2 (en) 1997-09-29 1999-04-08 Dasseux Jean Louis Gene therapy approaches to supply apolipoprotein a-i agonists and their use to treat dyslipidemic disorders
US7189689B2 (en) 1997-09-29 2007-03-13 Jean-Louis Dasseux Apolipoprotein A-L agonists and their use to treat dyslipidemic disorders
US6573239B1 (en) 1997-09-29 2003-06-03 Jean-Louis Dasseux Apolipoprotein A-I agonist compounds
US6518412B1 (en) 1997-09-29 2003-02-11 Jean-Louis Dasseux Gene therapy approaches to supply apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
US6602854B1 (en) 1997-09-29 2003-08-05 Jean-Louis Dasseux Branched multimeric Apo A-I agonist compounds
US6329341B1 (en) 1997-09-29 2001-12-11 Esperion Therapeutics, Inc. Method of treating septic shock
US6265377B1 (en) 1997-09-29 2001-07-24 Jean-Louis Dasseux Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
US7211565B2 (en) 1997-09-29 2007-05-01 Jean-Louis Dasseux Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
US6004925A (en) 1997-09-29 1999-12-21 J. L. Dasseux Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
US6630450B1 (en) 1997-09-29 2003-10-07 Jean-Louis Dasseux Method of treating dyslipidemia
US6753313B1 (en) 1997-09-29 2004-06-22 Jean-Louis Dasseux Multimeric Apoa-I agonist compounds
US6376464B1 (en) 1997-09-29 2002-04-23 Esperion Therapeutics, Inc. Lipid complexes of APO A-1 agonist compounds
US6734169B2 (en) 1997-09-29 2004-05-11 Jean Louis Dasseux Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
WO1999016408A2 (en) 1997-09-29 1999-04-08 Dasseux Jean Louis Apolipoprotein a-i agonists and their use to treat dyslipidemic disorders
US6716816B1 (en) 1997-09-29 2004-04-06 Jean-Louis Dasseux Multimeric Apo A-I agonist compounds
US20030203842A1 (en) 1997-09-29 2003-10-30 Jean-Louis Dasseux Apolipoprotein A-l agonists and their use to treat dyslipidemic disorders
US6037323A (en) 1997-09-29 2000-03-14 Jean-Louis Dasseux Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
US6046166A (en) 1997-09-29 2000-04-04 Jean-Louis Dasseux Apolipoprotein A-I agonists and their use to treat dyslipidemic disorders
US6287590B1 (en) 1997-10-02 2001-09-11 Esperion Therapeutics, Inc. Peptide/lipid complex formation by co-lyophilization
US6455088B1 (en) 1997-10-02 2002-09-24 Jean-Louis Dasseux Peptide/lipid complex formation by co-lyophilization
US6555651B2 (en) 1997-10-09 2003-04-29 The Trustees Of Columbia University In The City Of New York Ligand binding site of rage and uses thereof
US6201165B1 (en) 1997-10-16 2001-03-13 Board Of Regents, University Of Texas System Transgenic animal models for cardiac hypertrophy and methods of use thereof
US6046319A (en) 1997-10-22 2000-04-04 University Technologies International, Inc. Antisense oligodeoxynucleotides regulating expression of TNF-α
US6191151B1 (en) 1997-11-12 2001-02-20 Howard M. Zik Therapy for herpes neurological viral conditions utilizing 1,4-dihydropyridine calcium channel blockers
US20030077641A1 (en) 1998-03-11 2003-04-24 Laskowitz Daniel T. Methods of suppressing microglial activation and systemic inflammatory responses
US6303619B1 (en) 1998-03-12 2001-10-16 University Of Virginia Meta-substituted acidic 8-phenylxanthine antagonists of A3 human adenosine receptors
US6506880B2 (en) 1998-03-17 2003-01-14 The Uab Research Foundation Synthetic peptides that enhance atherogenic lipoprotein uptake and lower plasma cholesterol
WO1999047566A1 (en) 1998-03-17 1999-09-23 The Uab Research Foundation Synthetic peptides that enhance ldl uptake
US20020128175A1 (en) 1998-03-17 2002-09-12 Anantharamaiah Gattadahalli M. Synthetic peptides that enhance atherogenic lipoprotein uptake and lower plasma cholesterol
US6846636B1 (en) 1998-05-15 2005-01-25 American National Red Cross Methods and compositions for HDL holoparticle uptake receptor
US6019739A (en) 1998-06-18 2000-02-01 Baxter International Inc. Minimally invasive valve annulus sizer
US6007995A (en) 1998-06-26 1999-12-28 Isis Pharmaceuticals Inc. Antisense inhibition of TNFR1 expression
EP1974747A1 (en) 1998-08-11 2008-10-01 Biogen Idec Inc. Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibody
JP2000136202A (en) 1998-10-06 2000-05-16 Commonwealth Biotechnologies Inc Novel heparin binding peptide
EP1616572A1 (en) 1998-11-09 2006-01-18 Biogen Idec, Inc. Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-CD20 antibody
US6228989B1 (en) 1998-11-13 2001-05-08 The Regents Of The University Of California Peptide substrates phosphorylated by P21-activated protein kinase
US6464975B2 (en) 1998-12-11 2002-10-15 The Research Foundation Of State University Of New York Compositions and methods for altering cell migration
US6013522A (en) 1999-02-23 2000-01-11 Isis Pharmaceuticals Inc. Antisense inhibition of human Smad1 expression
US6790953B2 (en) 1999-04-01 2004-09-14 Esperion Therapeutics, Inc. Ether compounds
US6506799B1 (en) 1999-04-01 2003-01-14 Esperion Therapeutics, Inc. Methods of treating cardiovascular diseases, dyslipidemia, dyslipoproteinemia, and hypertension with ether compounds
US6459003B1 (en) 1999-04-01 2002-10-01 Esperion Therapeutics, Inc. Ether compounds
US6410802B1 (en) 1999-04-01 2002-06-25 Esperion Therapeutics, Inc. Methods for synthesizing ether compounds and intermediates therefor
US6646170B2 (en) 1999-04-01 2003-11-11 Esperion Therapeutics, Inc. Intermediates for the synthesis of ether compounds
US7192940B2 (en) 1999-04-01 2007-03-20 Esperion Therapeutics, Inc. Ether compounds
US6909014B2 (en) 1999-04-01 2005-06-21 Esperion Therapeutics, Inc. Intermediates for the synthesis of ether compounds
US6831105B2 (en) 1999-04-01 2004-12-14 Esperion Therapeutics, Inc. Compositions comprising ether compounds and pharmaceutical uses therefor
US6849714B1 (en) 1999-05-17 2005-02-01 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US20020142369A1 (en) 1999-05-19 2002-10-03 Fersht Alan Roy Refolding method of thrombin
US6025198A (en) 1999-06-25 2000-02-15 Isis Pharmaceuticals Inc. Antisense modulation of Ship-2 expression
US6033910A (en) 1999-07-19 2000-03-07 Isis Pharmaceuticals Inc. Antisense inhibition of MAP kinase kinase 6 expression
US6727063B1 (en) 1999-09-10 2004-04-27 Millennium Pharmaceuticals, Inc. Single nucleotide polymorphisms in genes
US6887470B1 (en) 1999-09-10 2005-05-03 Conjuchem, Inc. Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components
US6936691B2 (en) 1999-11-02 2005-08-30 Human Genome Sciences, Inc. Secreted protein HCE3C63
AU2673201A (en) 1999-12-20 2001-07-03 Ucb S.A. Alpha-arylethylpiperazine derivatives as neurokinin antagonists
US6514523B1 (en) 2000-02-14 2003-02-04 Ottawa Heart Institute Research Corporation Carrier particles for drug delivery and process for preparation
WO2001075170A1 (en) 2000-03-31 2001-10-11 The Regents Of The University Of California A functional assay of high-density lipoprotein
WO2001075067A2 (en) 2000-03-31 2001-10-11 Hyseq, Inc. Novel nucleic acids and polypeptides
US6869568B2 (en) 2000-03-31 2005-03-22 The Regents Of The University Of California Functional assay of high-density lipoprotein
WO2001075168A1 (en) 2000-03-31 2001-10-11 The Regents Of The University Of California Control of a gene induced by oxidized lipids in human artery wall cells
US20030040505A1 (en) 2000-03-31 2003-02-27 The Regents Of The University Of California Synthetic phospholipids to ameliorate atherosclerosis and other inflammatory conditions
US6444681B1 (en) 2000-06-09 2002-09-03 The Ohio State University Research Foundation Methods and compositions for treating Raynaud's Phenomenon and scleroderma
US6680203B2 (en) 2000-07-10 2004-01-20 Esperion Therapeutics, Inc. Fourier transform mass spectrometry of complex biological samples
US20020042441A1 (en) 2000-07-25 2002-04-11 Acton John J. N-substituted indoles useful in the treatment of diabetes
US7148197B2 (en) 2000-08-24 2006-12-12 The Regents Of The University Of California Orally administered small peptides synergize statin activity
EP1318828A1 (en) 2000-08-24 2003-06-18 The Regents of the University of California Orally administered peptides to ameliorate atherosclerosis
JP2006312650A (en) 2000-08-24 2006-11-16 Univ California Orally administered peptides that improve atherosclerosis
US7144862B2 (en) 2000-08-24 2006-12-05 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US20030045460A1 (en) 2000-08-24 2003-03-06 Fogelman Alan M. Orally administered peptides to ameliorate atherosclerosis
US20130295042A1 (en) 2000-08-24 2013-11-07 Uab Research Foundation Peptides and Peptide Mimetics to Treat Pathologies Associated With Eye Disease
US7166578B2 (en) 2000-08-24 2007-01-23 The Regents Of The University Of California Orally administered peptides synergize statin activity
US8568766B2 (en) 2000-08-24 2013-10-29 Gattadahalli M. Anantharamaiah Peptides and peptide mimetics to treat pathologies associated with eye disease
US8048851B2 (en) 2000-08-24 2011-11-01 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US7994132B2 (en) 2000-08-24 2011-08-09 The Regents Of The University Of California Peptides for treatment of scleroderma
US7820784B2 (en) 2000-08-24 2010-10-26 The Regents Of The University Of California Orally administered peptides synergize statin activity
US20070032430A1 (en) 2000-08-24 2007-02-08 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US20070060527A1 (en) 2000-08-24 2007-03-15 The Regents of the University of California and Orally administered small peptides synergize statin activity
US7807640B2 (en) 2000-08-24 2010-10-05 The Regents Of The University Of California Orally administered peptides synergize statin activity
US7723303B2 (en) 2000-08-24 2010-05-25 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US7199102B2 (en) 2000-08-24 2007-04-03 The Regents Of The University Of California Orally administered peptides synergize statin activity
CA2420222A1 (en) 2000-08-24 2002-02-28 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US7531514B2 (en) 2000-08-24 2009-05-12 The Regents Of The University Of California Orally administered peptides synergize statin activity
WO2002015923A1 (en) 2000-08-24 2002-02-28 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
CN1739787A (en) 2000-08-24 2006-03-01 加利福尼亚大学董事会 Orally administered peptides for improving atherosclerosis
CN1943781A (en) 2000-08-24 2007-04-11 加利福尼亚大学董事会 Orally administered peptides to ameliorate atherosclerosis
US20040266671A1 (en) 2000-08-24 2004-12-30 The Regents Of The University Of California Orally administered peptides synergize statin activity
CN1469754A (en) 2000-08-24 2004-01-21 ���������Ǵ�ѧ���»� Orally administered peptides for ameliorating atherosclerosis
AU2001286732B2 (en) 2000-08-24 2005-10-06 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US20070254839A1 (en) 2000-08-24 2007-11-01 The Regents Of The University Of California Orally administered peptides synergize statin activity
US6664230B1 (en) 2000-08-24 2003-12-16 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US6933279B2 (en) 2000-08-24 2005-08-23 The Regents Of The University Of California Orally administered peptides to ameliorate atherosclerosis
US20030229015A1 (en) 2000-08-24 2003-12-11 The Regents Of The University Of California Orally administered peptides synergize statin activity
US20080096815A1 (en) 2000-08-24 2008-04-24 The Regents Of The University Of California Orally administered peptides synergize statin activity
US20080095821A1 (en) 2000-08-24 2008-04-24 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US20080096816A1 (en) 2000-08-24 2008-04-24 The Regents Of The University Of California Orally administered peptides synergize statin activity
US20080096814A1 (en) 2000-08-24 2008-04-24 The Regents Of The University Of California Orally administered peptides synergize statin activity
US20080045459A1 (en) 2000-08-24 2008-02-21 The Regents Of The University Of California Orally administered peptides synergize statin activity
US6383808B1 (en) 2000-09-11 2002-05-07 Isis Pharmaceuticals, Inc. Antisense inhibition of clusterin expression
EP1186299A1 (en) 2000-09-12 2002-03-13 Universitair Medisch Centrum Utrecht The diagnosis, prevention, and/or succesful treatment of atherosclerosis, infectious diseases, and disturbances in the immune system
US6713507B2 (en) 2000-10-11 2004-03-30 Esperion Therapeutics, Inc. Ether compounds and compositions for cholesterol management and related uses
US6673780B2 (en) 2000-10-11 2004-01-06 Esperion Therapeutics, Inc. Sulfoxide and bis-sulfoxide compounds and compositions for cholesterol management and related uses
US6703422B2 (en) 2000-10-11 2004-03-09 Esperion Therapeutics, Inc. Sulfide and disulfide compounds and compositions for cholesterol management and related uses
US20040122091A1 (en) 2000-10-11 2004-06-24 Esperion Therapeutics, Inc. Sulfoxide and bis-sulfoxide compounds and compositions for cholesterol management and related uses
US6699910B2 (en) 2000-10-11 2004-03-02 Esperion Therapeutics, Inc. Ketone compounds and compositions for cholesterol management and related uses
US6982348B2 (en) 2001-01-26 2006-01-03 Takeda Pharmaceutical Company Limited Aminoethanol derivatives
US20040059110A1 (en) 2001-02-02 2004-03-25 Ajinomoto Co., Inc. Novel cystine derivative and agent for suppressing activation of inflammatory factors
US20030027769A1 (en) 2001-02-16 2003-02-06 Scialdone Mark A. Angiogenesis-inhibitory tripeptides, compositions and their methods of use
US7217785B2 (en) 2001-05-09 2007-05-15 The Regents Of The University Of California Cysteine-containing peptides having antioxidant properties
US20030087819A1 (en) 2001-05-09 2003-05-08 Bielicki John K. Cysteine-containing peptides having antioxidant properties
WO2002098446A1 (en) 2001-06-04 2002-12-12 Nobex Corporation Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same
EP1406656A2 (en) 2001-06-08 2004-04-14 Abbott Biotechnology Ltd METHODS OF ADMINISTERING ANTI-TNF$g(a) ANTIBODIES
US20060217307A1 (en) 2001-06-26 2006-09-28 Biomarck Pharmaceuticals, Ltd. Methods for regulating inflammatory mediators and peptides useful therein
US20030109442A1 (en) 2001-09-28 2003-06-12 Esperion Therapeutics, Inc. Prevention and treatment of restenosis by local administration of drug
US20030125260A1 (en) 2001-10-31 2003-07-03 Fortuna Haviv Tetra-and pentapeptides having antiangiogenic activity
US20040266663A1 (en) 2001-12-07 2004-12-30 Schwartz Daniel M. Methods to increase reverse cholesterol transport in the retinal pigment epithelium (RPE) and bruch's membrane (BM)
US7470660B2 (en) 2001-12-07 2008-12-30 The Regents Of The University Of California Treatment for dark adaptation
US20050197381A1 (en) 2001-12-13 2005-09-08 Longgui Wang Methods of treating an inflammatory-related disease
US8568799B2 (en) 2002-03-22 2013-10-29 Unigen, Inc. Isolation of a dual COX-2 and 5-lipoxygenase inhibitor from acacia
US6930085B2 (en) 2002-04-05 2005-08-16 The Regents Of The University Of California G-type peptides to ameliorate atherosclerosis
WO2003086326A2 (en) 2002-04-05 2003-10-23 The Regents Of The University Of California G-type peptides to ameliorate atherosclerosis
US7638494B2 (en) 2002-04-05 2009-12-29 The Regents Of The University Of California G-type peptides to ameliorate atherosclerosis
WO2003089612A2 (en) 2002-04-17 2003-10-30 University Of Florida Research Foundation, Inc. IMPROVED rAAV VECTORS
US20060292117A1 (en) 2002-04-17 2006-12-28 Loiler Scott A Improved rAAv vectors
US20040136989A1 (en) 2002-07-19 2004-07-15 Abbott Laboratories S.A. Treatment of vasculitides using TNFalpha inhibitors
WO2004027027A2 (en) 2002-09-18 2004-04-01 Trustees Of The University Of Pennsylvania Method of inhibiting choroidal neovascularization
WO2004034977A2 (en) 2002-10-16 2004-04-29 The Regents Of The University Of California Orally administered peptides synergize statin activity
EP1562624A2 (en) 2002-10-16 2005-08-17 The Regents Of The University Of California Orally administered peptides synergize statin activity
WO2004043396A2 (en) 2002-11-09 2004-05-27 Nobex Corporation Modified carbamate-containing prodrugs and methods of synthesizing same
AU2003290825A1 (en) 2002-11-13 2004-06-03 The Uab Research Foundation Synthetic single domain polypeptides mimicking apolipoprotein e and methods of use
US7563771B2 (en) 2002-11-13 2009-07-21 Uab Research Foundation Synthetic single domain polypeptides mimicking apolipoprotein E
CA2514303A1 (en) 2002-11-13 2004-05-27 The Uab Research Foundation Synthetic single domain polypeptides mimicking apolipoprotein e and methods of use
WO2004043403A2 (en) 2002-11-13 2004-05-27 The Uab Research Foundation Synthetic single domain polypeptides mimicking apolipoprotein e and methods of use
NZ541504A (en) 2002-11-13 2009-04-30 Uab Research Foundation Synthetic single domain polypeptides mimicking apolipoprotein E and methods of use
EP1599173A2 (en) 2002-11-13 2005-11-30 The Uab Research Foundation Synthetic single domain polypeptides mimicking apolipoprotein e and methods of use
US20070101448A1 (en) 2002-11-13 2007-05-03 Anantharamiah Gattadahalli M Synthetic single domain polypeptides mimicking apolipoprotein E and methods of use
US8084423B2 (en) 2002-11-13 2011-12-27 Uab Research Foundation Synthetic single domain polypeptides mimicking apolipoprotein E and methods of use
US20040186057A1 (en) 2002-11-13 2004-09-23 Anantharamiah Gattadahalli M. Synthetic single domain polypeptides mimicking apolipoprotein E and methods of use
US20060205634A1 (en) 2002-12-04 2006-09-14 Atul Varadhachary Lactoferrin in the reduction of circulating cholesterol, vascular inflammation, atherosclerosis and cardiovascular disease
US20040152623A1 (en) 2002-12-04 2004-08-05 Atul Varadhachary Lactoferrin in the reduction of circulating cholesterol, vascular inflammation, atherosclerosis and cardiovascular disease
US20060217298A1 (en) 2003-02-04 2006-09-28 Srivastava Pramod K Immunogenic cd91 ligand-antigenic molecule complexes and fusion proteins
US20050070996A1 (en) 2003-04-08 2005-03-31 Dinh Thomas Q. Drug-eluting stent for controlled drug delivery
US7291590B2 (en) 2003-06-12 2007-11-06 Queen's University At Kingston Compositions and methods for treating atherosclerosis
WO2005016280A2 (en) 2003-08-11 2005-02-24 The Regents Of The University Of California Orally administered small peptides synergize statin activity
US20050164950A1 (en) 2003-08-11 2005-07-28 The Regents Of The University Of California Orally administered small peptides synergize statin activity
US7148199B2 (en) 2003-09-26 2006-12-12 University Of Florida Research Foundation, Inc. Arginyl-glutamine dipeptide for treatment of pathological vascular proliferation
US20050239136A1 (en) 2003-12-05 2005-10-27 Hazen Stanley L Risk markers for cardiovacular disease
US20050154046A1 (en) 2004-01-12 2005-07-14 Longgui Wang Methods of treating an inflammatory-related disease
US20060069030A1 (en) 2004-07-16 2006-03-30 Trustees Of Tufts College Apolipoprotein A1 mimetics and uses thereof
WO2006020652A2 (en) 2004-08-11 2006-02-23 The Regents Of The University Of California Orally administered small peptides synergize statin activity
US20060173067A1 (en) 2004-08-11 2006-08-03 The Regents Of The University Of California Small molecules for the treatment of atherosclerosis
US8288335B2 (en) 2004-09-02 2012-10-16 Cognosei, Inc. ApoE analogs and methods for their use
EP1799242A2 (en) 2004-09-16 2007-06-27 The Regents of the University of California G-type peptides and other agents to ameliorate atherosclerosis and other pathologies
AU2005287004A1 (en) 2004-09-16 2006-03-30 The Regents Of The University Of California G-type peptides and other agents to ameliorate atherosclerosis and other pathologies
WO2006034056A2 (en) 2004-09-16 2006-03-30 The Regents Of The University Of California G-type peptides and other agents to ameliorate atherosclerosis and other pathologies
CA2580501A1 (en) 2004-09-16 2006-03-30 The Regents Of The University Of California G-type peptides and other agents to ameliorate atherosclerosis and other pathologies
US20060205669A1 (en) 2004-09-16 2006-09-14 The Regents Of The University Of California G-type peptides and other agents to ameliorate atherosclerosis and other pathologies
US8236754B2 (en) 2004-12-06 2012-08-07 The Regents Of The University Of California Methods for improving the structure and function of arterioles
US20060234908A1 (en) 2004-12-06 2006-10-19 The Regents Of The University Of California Methods for improving the structure and function of arterioles
WO2006063132A2 (en) 2004-12-06 2006-06-15 The Regents Of The University Of California Methods for improving the structure and function of arterioles
US7579319B2 (en) 2004-12-06 2009-08-25 The Regents Of The University Of California Methods for improving the structure and function of arterioles
US20090286741A1 (en) 2004-12-06 2009-11-19 The Regents Of The University Of California Methods for improving the structure and function of arterioles
US7427662B2 (en) 2005-02-01 2008-09-23 Baord Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Inhibition of angiogenesis and destruction of angiogenic vessels by apolipoprotein A-I and high density lipoprotein
US20060172919A1 (en) 2005-02-01 2006-08-03 Hornick Conrad A Inhibition of angiogenesis and destruction of angiogenic vessels by apolipoprotein A-I and high density lipoprotein
WO2006118805A2 (en) 2005-04-29 2006-11-09 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US20080293639A1 (en) 2005-04-29 2008-11-27 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US20070071756A1 (en) 2005-09-26 2007-03-29 Peyman Gholam A Delivery of an agent to ameliorate inflammation
WO2008143679A2 (en) 2006-06-01 2008-11-27 Verenium Corporation Nucleic acids and proteins and methods for making and using them
US20090163408A1 (en) 2006-08-08 2009-06-25 The Regents Of The University Of California Salicylanilides enhance oral delivery of therapeutic peptides
WO2008021088A2 (en) 2006-08-08 2008-02-21 The Regents Of The University Of Californina Salicylanilides enhance oral delivery of therapeutic peptides
US8148328B2 (en) 2006-08-08 2012-04-03 The Regents Of The University Of California Salicylanilides enhance oral delivery of therapeutic peptides
EP2195340A2 (en) 2007-08-28 2010-06-16 UAB Research Foundation Synthetic apolipoprotein e mimicking polypeptides and methods of use
US8557767B2 (en) 2007-08-28 2013-10-15 Uab Research Foundation Synthetic apolipoprotein E mimicking polypeptides and methods of use
US20100286025A1 (en) 2007-08-28 2010-11-11 Anantharamaiah Gattadahalli M Synthetic apolipoprotein e mimicking polypeptides and methods of use
US20100298215A1 (en) 2007-08-28 2010-11-25 Anantharamaiah Gattadahalli M Synthetic apolipoprotein e mimicking polypeptides and methods of use
JP2010537638A (en) 2007-08-28 2010-12-09 ユーエービー リサーチ ファウンデーション Synthetic apolipoprotein E mimetic polypeptides and methods of use
JP2010538005A (en) 2007-08-28 2010-12-09 ユーエービー リサーチ ファウンデーション Synthetic apolipoprotein E mimetic polypeptides and methods of use
EP2682400A1 (en) 2007-08-28 2014-01-08 Uab Research Foundation Synthetic apolipoprotein E mimicking polypeptides and methods of use
EP2195331A2 (en) 2007-08-28 2010-06-16 UAB Research Foundation Synthetic apolipoprotein e mimicking polypeptides and methods of use
CA2704729A1 (en) 2007-08-28 2009-03-12 Uab Research Foundation Synthetic apolipoprotein e mimicking polypeptides and methods of use
WO2009032693A2 (en) 2007-08-28 2009-03-12 Uab Research Foundation Synthetic apolipoprotein e mimicking polypeptides and methods of use
WO2009032702A2 (en) 2007-08-28 2009-03-12 Uab Research Foundation Synthetic apolipoprotein e mimicking polypeptides and methods of use
AU2008296487A1 (en) 2007-08-28 2009-03-12 The Uab Research Foundation Synthetic apolipoprotein E mimicking polypeptides and methods of use
US20120245101A1 (en) 2007-08-28 2012-09-27 Anantharamaiah Gattadahalli M Synthetic apolipoprotein e mimicking polypeptides and methods of use
AU2008296478A1 (en) 2007-08-28 2009-03-12 The Uab Research Foundation Synthetic apolipoprotein E mimicking polypeptides and methods of use
CA2697957A1 (en) 2007-08-28 2009-03-12 Uab Research Foundation Synthetic apolipoprotein e mimicking polypeptides and methods of use
WO2009073725A2 (en) 2007-12-04 2009-06-11 The Regents Of The University Of California Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
CA2714082A1 (en) 2008-02-07 2009-08-13 Uab Research Foundation Peptides and peptide mimetics to treat pathologies associated with eye disease
WO2009100348A2 (en) 2008-02-07 2009-08-13 Uab Research Foundation Peptides and peptide mimetics to treat pathologies associated with eye disease
US20110182992A1 (en) 2008-02-07 2011-07-28 Anantharamaiah Gattadahalli M Peptides and peptide mimetics to treat pathologies associated with eye disease
US20130005645A1 (en) 2010-01-06 2013-01-03 Vitek Michael P Apoe peptide dimers and uses thereof
EP2996706A1 (en) 2013-03-14 2016-03-23 The UAB Research Foundation Apolipoprotein mimetics and uses thereof
WO2014152776A1 (en) 2013-03-14 2014-09-25 Uab Research Foundation Apolipoprotein mimetics and uses thereof
AU2014239186A1 (en) 2013-03-14 2015-10-08 Lipimetix Development, Llc Apolipoprotein mimetics and uses thereof
US20160002315A1 (en) 2013-03-14 2016-01-07 Uab Research Foundation Apolipoprotein mimetics and uses thereof
AU2017203911A1 (en) 2013-03-14 2017-06-29 Lipimetix Development, Llc Apolipoprotein mimetics and uses thereof
JP2016515137A (en) 2013-03-14 2016-05-26 ユーエイビー リサーチ ファンデーション Apolipoprotein mimics and uses thereof
JP2017505143A (en) 2014-02-10 2017-02-16 アンプテック ゲゼルシャフト ミット ベシュレンクテル ハフツング Incoded RNA
WO2016018665A1 (en) 2014-07-31 2016-02-04 Uab Research Foundation Apoe mimetic peptides and higher potency to clear plasma cholesterol
AU2015298263A1 (en) 2014-07-31 2017-03-16 Anji Pharmaceuticals, Inc. Apoe mimetic peptides and higher potency to clear plasma cholesterol
MX2017001432A (en) 2014-07-31 2017-05-09 Uab Res Found MIMETIC PEPTIDES OF THE APOE AND GREATER POWER TO CLEAN THE CHOLESTEROL IN PLASMA.
CA2954475A1 (en) 2014-07-31 2016-02-04 Uab Research Foundation Apoe mimetic peptides and higher potency to clear plasma cholesterol
BR112017001860A2 (en) 2014-07-31 2018-02-27 Uab Research Foundation synthetic peptide, pharmaceutical composition, methods, dosage regimen, and monoclonal antibody
IL250302B (en) 2014-07-31 2022-07-01 Uab Research Foundation Apoe mimetic peptides with high potency to clear plasma cholesterol
WO2016028665A1 (en) 2014-08-22 2016-02-25 Corning Optical Communications LLC Optical fiber cable with print protective outer surface profile

Non-Patent Citations (1876)

* Cited by examiner, † Cited by third party
Title
Abrahmsen, L. et al. (1991) Engineering Subtilisin and its Substrates for Efficient Ligation of Peptide Bonds in Aqueous Solution. Biochemistry. 30(17): 4151-9.
Acsadi, G. et al. (1991) Human Dystrophin Expression in MDX mice after Intramuscular Injection of DNA Constructs. Nature. 352(6338): 815-8.
Adachi, T. et al. (2003) Binding oh Human Xanthine Oxidase to Sulphated Glycosaminoglycans on the Endothelial-Cell Surface. Biochemistry. 289(2): 523-7.
Advisory Action dated Aug. 13, 2007 for U.S. Appl. No. 10/712,447 (3 pages).
Advisory Action issued Aug. 13, 2007 for U.S. Appl. No. 10/712,447 (3 pages).
Aikawa, M. et al. (2002) Lipid Loweing Reduces Oxidative Stress and Endothelial Cal Activation in Rabbit Atheroma. Circulation. 106(11): 1390-6.
Ajees, A.A. et al. (2006) Crystal Structure of Human Apolipoprotein A-1: Insights into its Protective Effect Against Cardiovascular Diseases. Proc Natl Acad Sci USA. 103(7): 2126-31.
Ali, K. et al. (2005) Apoliopoprotein E Suppresses the Type 1 Inflammatory Response in Vivo. Circ Res. 97(9): 922-7.
Almquist et al., Synthesis and Biological Activity of a Ketomethylene Analogue of a Tripeptide Inhibitor of Angiotensin Converting Enzyme. J Med Chem. 1980; 23(12):1392-8.
Anantharamaiah, G.M. et al. (1985) Studies of Synthetic Peptide Analogs of the Amphipathic Helix: Structure of Complexes with Dimyristoyl Phosphatidylcholine. J Biol Chem. 260(18): 10248-55.
Anantharamaiah, G.M. et al. (1988) Effect of Oxidation on the Properties of Apolipoproteins A-I and A-II. J Lipid Res. 29(3): 309-18.
Anantharamaiah, G.M. et al. (1990) Use of Synthetic Peptide Analogues to Localize Lecithin: Cholesterol Acyltransferase Activating Domain in Apolipoprotein A-I. Ateriosclerosis. 10(1): 95-105.
Anantharamaiah, G.M. et al. (2001) Toward the Design of Peptide Mimics of Antiatherogenic Apolipoproteins A-I and E. Curr Sci. 81(1): 53-65.
Anantharamaiah, G.M. et al. (2006) Synthetic Peptides: Managing Lipid Disorders. Curr Opin Lipidol. 17(3): 233-7.
Anantharamaiah, G.M. et al. (2007) Structural Requirements for Antioxidative and Anti-Inflammatory Properties of Apolipoprotein A-I Mimetic Peptides. J Lipid Res. 48(9): 1915-23.
Anantharamaiah, G.M., Synthetic Peptide Analogs of Apolipoproteins. Meth Enzymol. 1986; 128:627-47.
Aoyagi, H. et al. (1988) Sytheses of Antibacterial Peptides, Gramicidin S Analogs and Designed Amphiphilic Oligopeptides. Tetrahedron. 44(3):877-86.
Applicant-Initiated Interview Summary dated Jun. 26, 2018 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (3 pages).
Applicant-Initiated Interview Summary issued on Jun. 26, 2018 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (3 pages).
Aravinda, S. et al. (2003) Aromatic-Aromatic Interactions in Crystal Structures of Helical Peptide Scaffolds Containing Projecting Phenylalinine Residues. J Am Chem Soc. 125(18): 5308-15.
Arisaph Pharmaceuticals Reports on Promising Results Presented at American Heart Association: Novel Apo A-1-Mimetic Peptide Significantly Inhibits Atherosclerosis in Preclinical Animal Study, BioSpace News, (Nov. 14, 2005) (2 pages). http://www.biospace.com/News/arisaph-pharmaceuticals-reports-on-promising/2610.
Arisaph Pharmaceuticals Reports on Promising Results Presented at American Heart Association: Novel Apo A-I-Mimetic Peptide Significantly Inhibits Atherosclerosis in Preclinical Animal Study, BioSpace News, (Nov. 14, 2005) (2 pages). http://www.biospace.com/News/arisaph-pharmaceuticals-reports-on-promising/2610.
Armitage, B. et al., Peptide Nucleic Acid-DNA Duplexes: Long Range Hole Migration from an Internally Linked Anthraquinone, Proc Natl Acad Sci USA, 94(23): 12320-5 (1997).
Ashby, D. et al., Lack of Effect of Serum Amyloid A (SAA) on the Ability of High-Density Lipoproteins to Inhibit Endothelial Cell Adhesion Molecule Expression, Atherosclerosis, 154(1): 113-21 (2001).
Ashby, D.T. et al., Factors influencing the Ability of HDL to Inhibit Expression of Vascular Cell Adhesion Molecule-1 in Endothelial Cells, Arterioscler Thromb Vasc Biol, 18(9): 1450-5 (1998).
Badimon, J.J. et al., Regression of Atherosclerosis Lesions by High Density Lipoprotein Plasma Fraction in the Cholesterol-Fed Rabbit, J Clin Invest, 85(4): 1234-41 (1990).
Baggiolini, M and I. Clark-Lewis, Interlukin-8, a Chemotactic and Inflammatory Cytokine, FEBS Lett, 307: 97-101 (1992).
Bailey, R.W. et al., Clusterin, a Binding Protein with a Molten Globule-Like Region, Biochemistry, 40(39): 11828-40 (2001).
Baker, P.W. et al., Ability of Reconstituted High Density Lipoproteins to Inhibit Cytokine-Induced Expression of Vascular Cell Adhesion Molecule-1 in Human Umbilical Vein Endothelial Cells, J Lipid Res, 40(2): 345-53 (1999).
Baker, P.W. et al., Phospholipid Composition of Reconstituted High Density Lipoproteins Influences Their Ability to Inhibit Endothelial Cell Adhesion Molecule Expression, J Lipid res, 41(8):1261-7 (2000).
Barengolts et al., Osteoporosis and Coronary Atherosclerosis in Asymptomatic Postmenopausal Woman, Calcif Tissue Int, 62(3):209-13 (1998).
Barter, P.J. and K.A. Rye, High Density Lipoproteins and Coronary Heart Disease, Atherosclerosis, 121(1): 1-12 (1996).
Baumbach et al., Cerebral Arteriolar Structure in Mice Overexpressing Human Renin and Angiotensinogen, Hypertension, 41(1): 50-5 (2003).
Baumbach et al., Structure of Cerebral Arterioles in Cystathionine β-Synthase-Deficient Deficient Mice, Circ res, 91(10): 931-7 (2002).
Baumbach et al., Structure of Cerebral Arterioles in Cystathionine β-Synthase-Deficient Mice, Circ res, 91(10): 931-7 (2002).
Beatty S, Koh H, Phil M, Henson D, Boulton M. (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 45(2):115-134.
Bechinger B. (2000) Understanding peptide interactions with the lipid bilayer: a guide to membrane protein engineering. Curr Opin Chem Biol. 4(6):639-644.
Beisiegel, U. et al. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature 341: 162-164 (1989).
Bergt, C. et al., (2004) The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Natl Acad Sci USA. 101:13032-7.
Berkner et al. (1987) Abundant Expression of Polyomavirus Middle T Antigen and Dihydrofolate Reductase in an Adenovirus Recombinant. J. Virology 61:1213-1220.
Besiegel, U. et al. (1991) Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein Proc. Natl. Acad. Sci. U.S.A. 88:8342-8346.
Betteridge, D.J., Long-term risk reduction: Who needs treatment?, Diabetes Research and Clinical Practice. (2005) 68S2:S15-2.
Bisoendial et al. (2003) Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low High-Density Lipoprotein Circulation 107: 2944-2948.
Blackburn WD Jr, et al. (1991) Apolipoprotein A-I decreases neutrophil degranulation and superoxide production. J Lipid Res. 32(12): 1911-1918.
Blankenberg et al. (2001) Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 2001; 104:1336-1342.
Boerner et al. (1991) Production of Antigen-Specific Human Monoclonal Antibodies from in Vitro-Primed Human Splenocytes. J. Immunol., 147(1):86-95.
Boffa et al., Isolation of active genes containing CAG repeats by DNA strand invasion by a peptide nucleic acid. Proc Natl Acad Sci USA. Mar. 14, 1995; 92(6): 1901-5.
Boffelli et al. (1997) Reconstitution and Further Characterization of the Cholesterol Transport Activity of the Small-Intestinal Brush Border Membrane Biochemistry 36:10784-10792.
Boffelli et al., (1997) The uptake of cholesterol at the small-intestinal brush border membrane is inhibited by apolipoproteins. FEBS Letters, 411: 7-11.
Borhani et al. (1999) Crystal structure of truncated human apolipoprotein A-1 suggests a lipid bound conformation. Proc. Natl. Acad. Sci. USA. 94:12291-12296.
Bourdillon et al. (2000) ICAM 1 deficiency reduces atherosclerotic lesions in double-knockout mice (ApoE(-/ ) IICAM-1(-/-)) fed a fat or a chow diet. Arterioscler Thromb Vasc Biol 2000;20:2630-2635.
Bowry et al. (1992) High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors. Proc Natl Acad Sci USA. 1992;89:10316-10320.
Braddock. D. T., et al., (1996) Conformationally Specific Enhancement of Receptor-ediated LDL Binding and Internalization by Peptide Models of a Conserved Anionic N-Termina Domain of Human Apolipoprotein E. Biochemistry 35, 13975-13984.
Bradley et al. (1982) Apolipoprotein E degradation in human very low density lipoproteins by protease(s): chemical and biological consequences. Biochim. Biophys. Res. Commun. 109:1360-1367.
Bradley, W.A. and S.H. Gianturco, ApoE is Necessary and Sufficient for the Bidning of Large Triglyceride-Rice Lioproteins to the LDL Receptor; ApoB is Unnecessary. J Lipid Res. 1986; 27(1):40-8.
Brigham et al. (1989) Expression of a prokaryotic gene in cultured lung endothelial cells after lipofection with a plasmid vector. Am. J. Resp. Cell. Mol. Biol. 1: 95-100.
Brousseau, M.E. (2005) Emerging role of high-density lipoprotein in the prevention of cardiovascular disease. Drug Discovery Today. 10:1095-1099.
Brousseau, M.E., and Hoeg, J.M. (1999) Transgenic rabbits as models for atherosclerosis research. J. lipid Res. 40:365-375.
Brown M.L., et al. (2000) A Macrophage Receptor for Apolipoprotein B48: Clining, Expression, and Atherosclerosis. Proc. Natl. Acad. Sci. USA 97:7488-7493.
Brown, B.G. et al. (2001) Simvastatin and Niacin, Antioxidant Vitamins, or the Combination for the Prevention of Coronary Disease. N Engl J Med. 345(22):1583-92.
Brown, D.T. and Burlingham, B.T., (1973) Penetration of Host Cell Membranes by Adenovirus 2 J. Virology 12:386-396.
Burger et al. (2002) High-density lipoprotein-associated apolipoprotein A-I: the missing link between infection and chronic inflammation?Autoimmunity Reviews 2002;1:111-117.
Burnett, J.R. and Vasikaran, S.D. (2002) Cardiovascular disease and osteoporosis: is there a link between lipids and bone? Ann Clin Biochem. 39(Pt 3): 203-210.
Calabresi L, et al. (2002) Elevated cellular adhesion molecules in subjects with low ML-cholesterol. Arterioscler Thromb Vasc Biol.;22:656-661.
Calabresi L, Franceschini G, Sirtoh CR, De Palma A, Saresella M, Ferrante P, Taramelli D. Inhibition of VCAM-1 expression in endothelial cells by reconstituted high density lipoproteins. Biochem Biophys Res Commun. (1997) 238:61-65.
Calabresi, L., et al., (2003) Entothelial Protection by High-Denisty Lipoproteins. Athero. Thromb. Vasc. Biol. 23:1724-1731.
Campbell, E.J. Human leukocyte elastase, cathepesin G and lactoferrin: family of neutrophil granule glycoproteins that bind to an alveolar macrophage receptor. Proc Natl Acad Sci USA (1982) 79:6941-6945.
Cardillo, C. et al., (1997) Xanthine Oxidase Inhibition With Oxypurinol Improves Endothelial Vasodilator Function in Hypercholesterolemic but Not in Hypertensive Patients. Hypertension 30:57-63.
Carlos TM, et al. (1990) Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood;76:965-970.
Carr, A.C. et al. (2000) Oxidation of LDL by myeloperoxidase and reactive nitrogen species oxidation of LDL by myeloperoxidase and reactive nitrogen species. Arterioscler Thromb Vasc Biol; 20:1716-1723.
Carrara et al., Two helices plus a linker: A small model substrate for eukaryotic RNase P Proc. Natl. Acad. Sci. (USA) 92:2627-2631 (1995).
Casserly, I. and Topol, E. (2004) Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins. Lancet. 363:1139-46.
Castelli, W.P. et al., Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham study. JAMA. 1986. 256:2835-8. Abstract.
Catapano, A.L. et al. (1979) Suppression of 3-hydroxy-3-methylglutaryl-CoA reductase by low density lipoproteins produced in vitro by lipoprotein lipase action on nonsuppressive very low density lipo-proteins. J Biol Chem. 254:1007-9.
Certificate of Correction dated Sep. 8, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Certificate of Correction issued Sep. 8, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Certificate of Grant dated Aug. 3, 2017 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Certificate of Grant dated Dec. 11, 2014 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (97 pages).
Certificate of Grant issued on Aug. 3, 2017 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Certificate of Grant issued on Dec. 11, 2014 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (97 pages).
Charles-Schoeman, C. et al. (2008) Treatment with an apolipoprotein A-1 mimetic peptide in combination with pravastatin inhibits collagen-induced arthritis. Clin Immunol. 127(2): 234-44.
Chiesa, G. et al. (2002) Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ Res. 90:974-80.
Chillon, J. and Baumbach, G.L. (1999) Effects of an Angiotensin-Converting Enzyme Inhibitor and a b-Blocker on Cerebral Arterioles in Rats. Hypertension. 33: 856-61.
Chorev, M. and Goodman, M. (1995) Recent developments in retro peptides and proteins-an ongoing topochemical exploration. Trends Biotechnol. 13(10): 438-45.
Christison J, (1996) Rapid reduction and removal of HDL- but not LDL-associated cholesteryl ester hydroperoxides by rat liver in situ. Biochem J. 314:739-42.
Chung et al., (1985) Studies of Synthetic Peptide Analogs of the Amphipathic Helix. J Biol Chem. 60(18): 10256-62.
Chung, B.H. et al. (1994) Liposome-like Particles Isolated From Human Atherosclerotic Plaques are Structurally and Compositionally Similar to Surface Remnants of Triglyceride-Rich Lipoproteins. Arterioscler Thromb. 14:622-35.
Chung, B.H., et al. (1996) Probing structure and function of VLDL by synthetic amphipathic helical peptides. J Lipid Res. 37:1099-112.
Clark-Lewis et al. (1991) Chemical Synthesis, Purification, and Characterization of Two Inflammatory Proteins, Neutrophil Activating Peptide 1 (Interleukin-8) and Neutrophil Activating Peptide 2. Biochemistry. 30: 3128-35.
Clark-Lewis I, et al. (1994) Structural requirements for interleukin-8 function identified by design of analogs and CXC chemokine hybrids. J Biol Chem. 269(23): 16075-81.
Clay, M.A. et al. (1995) Localization of a domain in apolipoprotein E with both cytostatic and cytotoxic activity. Biochemistry. 34:11142-51.
Clay, M.A. et al. (2001) Time sequence of the inhibition of endothelial adhesion molecule expression by reconstituted high density liproteins, Atherosclerosis 157: 23-9.
Clee, S.M. et al. (2000) Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 hetrozygotes. J Clin Invest. 106:1263-70.
Clubb, F.J., et al. (2001) Development of atherosclerotic plaque with endothelial disruption in Watanabe heritable hyperlipidemic rabbit aortas. Cardiovasc. Pathol. 9:1-11.
Cockerill, G.W. et al. (1995) High-density lipoproteins inhibit crone-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol. 15:1987-94 (22 pages).
Cockerill, G.W. et al. (1999) High-density lipoproteins differentially modulate cytokine induced expression of E-selectin and cyclooxygenase-2. Arterioscler Thromb Vasc Biol. 19:910-7.
Cockerill, G.W. et al. (2001) Elevation of plasma high-density lipoprotein concentration reduces interleukin-I induced expression of E-selectin in an in vivo model of acute inflammation. Rculation. 103:108-12.
Collard, M.W. and Griswold, M.D. (1987) Biosynthesis and molecular cloning of sulfated glycoprotein 2 secreted by rat Sertoli cells. Biochemistry. 26(12):3297-303.
Colles, S.M. et al. (2001) Oxidized LDL-induced injury and apoptosis in atherosclerosis. Potential roles for oxysterols. Trends Cardiovasc Med. 11:131-8.
Corey, D.R. (1997) Peptide nucleic acids: expanding the scope of nucleic acid recognition. Trends Biotechnol. 15(6):224-9.
Coyne, E.F. et al. (2002) Methods for isolation and characterization of intracerebral arterioles in the C57/13L6 wild-type mouse. J Neurosci Meth. 120:145-53.
Cubeddu, L.X. et al., Statin Withdrawal: Clinical Implications and Molecular Mechanisms. Pharmacotherapy. 2006; 26(9):1288-96.
Cuchel, M. et al., Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open label, phase 3 study. Lancet. 2013; 381(9860):40-6.
Curcio CA, et al. (2005) Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp Eye Res. 81(6): 731-41.
Curcio, C.A. et al. (2001) Accumulation of cholesterol with age in human Bruch's membrane. Invest Ophthalmol Vis Sci. 42(1):265-74.
Cybulsky MI, et al. (2001) a major role for VCAM-1, but not ICAM-I, in early atherosclerosis. J Clin Invest.107:1255-62.
Cyrus, et al., (2001) Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein E-deficient mice. Circulation. 103:2277-82.
Dai et al. (2004) Implantation of Immature Neonatal Cardiac Cells Into the Wall of the Aorta in Rats: A Novel Model for Studying Morphological and Functional Development of Heart Cells in an Extracardiac Environment. Circulation. 110(3):324-9.
Dai et al. (2005) Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation 112(2):214-23.
Dansky HM, et al. (1999) Apo A-I inhibits foam cell formation in Apo E-deficient mice after monocyte adherence to endothelium. J Clin Invest. 104:31-9.
Dansky HM, et al. (2001) Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler Thromb Vasc Biol. 21:1662-7.
Dashti et al. (2004) Model class A and class L peptides increase the production of apoA-I-containing lipoproteins in HepG2 cells. J Lipid Res. 45:1919-28.
Datta et al. (2000) The Receptor Binding Domain of Apolipoprotein E, Linked to a Model Class A Amphipathic Helix, Enhances Internalization and Degradation of LDL by Fibroblasts. Biochemistry. 30:213-20.
Datta et al. (2001) Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotcin metabolism in vitro and in vivo. J Lipid Res. 42:959-66.
Datta et al. (2001) Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo. J Lipid Res. 42:959-66.
Datta et al. (2001) Effects of Increasing Hydrophobicity on the Physical-Chemical and Biological Properties of a Class A Amphipathic Helical Peptide. J Lipid Res. 42(7):1096-104.
Datta, G. et al. (2004) Aromatic Residue Position on the Nonpolar Face of Class A Amphipathic Helical Peptides Determines Biological Activity. J Biol Chem. 279:26509-17.
Datta, G. et al. (2009) Anti-inflammatory and recycling properties of an apolipoprotein mimetic peptide, Ac-hE18A-NH(2). Atherosclerosis. 2008(1): 134 (24 pages).
Davenport, P. and Tipping, P.G. (2003) The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol 163:1117-25.
Davidson, D. et al. (1987) Overproduction of Polyomavirus Middle T Antigen in Mammalian Cells through the Use of an Adenovirus Vector. J Virology. 61:1226-39.
Davidson, et al. (1994) The Influence of Apolipoprotein Structure on the Efflux of Celluar Free Cholesterol to High Density Lipoprotein. J Biol Chem. 269(37):22975-82.
Dawson, P.E. et al. (1994) Synthesis of Proteins by Native Chemical Ligations. Science. 266:776-9.
De Caterina, R. et al. (1998) Structural requirements for inhibition of cytokine-induced endothelial activation by unsaturated fatty acids. J Lipid Res. 39:1062-70.
Diederich et al. (2001) Apolipoprotein Al and HDL3 Inhibit Spreading of Primary Human Monocytes through a Mechanism that Involves Cholesterol Depletion and Regulation of CD42. Atherosclerosis. 159:313-24.
Dimayuga, P. et al. (1999) Reconstituted HDL containing human apolipoprotein A-1 reduces VCAM-1 expression and neointima formation following periadventitial cuffinduced carotid injury in apoE null mice. Biochem Biophys Res Commun. 264:465-8.
Dithmar, S. et al. (2000) Ultrastructural changes in Bruch's membrane of apolipoprotein E-deficient mice. Invest Ophthalmol Vis Sci. 41(8): 2035-42.
Domanski, M.J., Primary Prevention of Coronary Artery Disease. N Engl J Med. 2007; 357(15): 1543-5.
Dooley, C.T. et al. (1994) An All D-Amino Acid Opioid Peptide with Central Analgesic Activity from a Combinatorial Library. Science. 266:2019-22.
Dunlop, D.S. and Neidle, A. (1997) The Origin and Turnover of D-Serine in Brain. Biochem Biophys Res Commun. 235:26-30.
Duong, P. T. et al. (2006). Characterization of nascent HDL particles and macroparticles formed by ABC A1-mediated cholesterol efflux of cellular lipids to apo A-I. J Lipid Res. 47:832-43.
Dyer, C. A. et al. (1991) Only Multimers of a Synthetic Peptide of Human Apolipoprotein E are Biologically Active. J Biol Chem. 266(23):15009-15.
Dyer, C. A. et al., (1995) Structural features of synthetic peptides of apolipoprotein E that bind the LDL receptor. J Lipid Res. 36:80-8.
Dyer, C.A. and L.K. Curtiss, A Synthetic Peptide Mimic of Plasma Apolipoprotein E that Binds the LDL Receptor. J Biol Chem. 1991; 266(34):22803-6.
Dyer, C.A. et al., Only Multimers of a Synthetic Peptide of Human Apolipoprotein E are Biologically Active. J Biol Chem. 1991; 266(23):15009-15.
Ehara et al. (2001) Elevated Levels of Oxidized Low Density Lipoprotein Show a Positive Relationship With the Severity of Acute Coronary Syndromes. Circulation. 103:1955-60.
Eisenberg et al. (1992) Lipoprotein lipase enhances binding of lipoproteins to heparan sulfate on cell surfaces and extracellular matrix. J Clin Invest. 90:2013-21.
Epand et al. (1987) Studies Synthetic Peptide Analog of the Amphipathic Helix J. Biol. Chem. 262(19): 9389-96.
Epand et al. (2004) An Apolipoprotein AI Mimetic Peptide: Membrane Interactions and the Role of Cholesterol. Biochemistry. 43:5073-83.
Epand et al. (2004) Two Homologous Apolipoprotein AI Mimetic Peptides: Relationship Between Membrane Interactions and Biological Activity. J Biol Chem. 279:51404-15.
Epand, R.M. et al. (1994) HDL and apolipoprotein A-I protect erythrocytes against the generation of procoagulant activity. Arterioscler Thromb. 14(11): 1775-83.
European Search Report dated Dec. 19, 2016 by the European Patent Office for Patent Application No. 14769489.7, which was filed on Mar. 14, 2014 and published as 2996706 on Mar. 23, 2016 (Applicant—UAB Research Foundation et al.) (8 pages).
European Search Report was issued on Dec. 19, 2016 by the European Patent Office for Patent Application No. 14769489.7, which was filed on Mar. 14, 2014 and published as 2996706 on Mar. 23, 2016 (Applicant—UAB Research Foundation et al.) (8 pages).
Ex Parte Quayle Action dated Aug. 14, 2009 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Ex Parte Quayle Action issued Aug. 14, 2009 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Examination Report and Notice of Acceptance of Completed Specification dated Apr. 7, 2009 for New Zealand Application No. 541504 (2 pages).
Examination Report and Notice of Acceptance of Completed Specification issued Apr. 7, 2009 for New Zealand Application No. 541504 (2 pages).
Examination Report dated for Aug. 5, 2008 New Zealand Application No. 541504 (2 pages).
Examination Report dated Jan. 22, 2009 for New Zealand Application No. 541504 (2 pages).
Examination Report dated Sep. 21, 2017 by the Canadian Intellectual Property Office for Patent Application No. 2903869, which was filed on Mar. 14, 2013 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (6 pages).
Examination Report dated Sep. 8, 2016 by the Canadian Intellectual Property Office for Patent Application No. 2903869, which was filed on Mar. 14, 2013 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (4 pages).
Examination Report issued for Aug. 5, 2008 New Zealand Application No. 541504 (2 pages).
Examination Report issued Jan. 22, 2009 for New Zealand Application No. 541504 (2 pages).
Examination Report issued on Sep. 21, 2017 by the Canadian Intellectual Property Office for Patent Application No. 2903869, which was filed on Mar. 14, 2013 (Invento—G.M. Anantharamaiah, et al.; Applican—UAB Research Foundation) (6 pages).
Examination Report issued on Sep. 8, 2016 by the Canadian Intellectual Property Office for Patent Application No. 2903869, which was filed on Mar. 14, 2013 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (4 pages).
Examination Report No. 1 dated Dec. 3, 2012 by the Intellectual Property Office of Australia for Australian Patent Application No. 2008296487, which was filed on Mar. 11, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 1 dated Nov. 9, 2012 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 1 issued on Dec. 3, 2012 by the Intellectual Property Office of Australia for Australian Patent Application No. 2008296487, which was filed on Mar. 11, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 1 issued on Nov. 9, 2012 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 2 dated Dec. 22, 2016 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—Uab Research Foundation) (3 pages).
Examination Report No. 2 dated Jan. 6, 2014 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Examination Report No. 2 issued on Dec. 22, 2016 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 2 issued on Jan. 6, 2014 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Examiner's First Report dated Apr. 30, 2008 for Australian Application No. 200390825 (2 pages).
Examiner's First Report issued Apr. 30, 2008 for Australian Application No. 200390825 (2 pages).
Extended European Search Report dated Dec. 3, 2013 by the European Patent Office for European Patent Application No. 13187186.5, which was filed on Oct. 7, 2013 and published as 2682400 on Jan. 8, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (10 pages).
Extended European Search Report dated Nov. 13, 2017 by the European Patent Office for patent application No. 17157243.1, which was filed on Feb. 21, 2017 and published as EP 3254673 on Dec. 13, 2017 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (7 pages).
Extended European Search Report issued on Dec. 3, 2013 by the European Patent Office for European Patent Application No. 13187186.5, which was filed on Oct. 7, 2013 and published as 2682400 on Jan. 8, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (10 pages).
Extended European Search Report issued on Nov. 13, 2017 by the European Patent Office for patent application No. 17157243.1, which was filed on Feb. 21, 2017 and published as EP 3254673 on Dec. 13, 2017 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (7 pages).
Farkas, M.H. et al. (2004) The recycling of apolipoprotein E and its amino-terminal 22kDA fragment: evidence for multiple redundant pathways. J Lipid Res. 45:1546-54.
Felgner et al. (1987) Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA. 84:7413-7.
Field et al. (2001) Gene expression of sterol regulatory element-binding proteins in hamster small intestine. J Lipid Res. 42:1-9.
Fielding and Fielding (1995) Molecular physiology of reverse cholesterol transport. J Lipid Res. 36:211-28.
Final Office Action dated Apr. 11, 2005 for U.S. Appl. No. 10/187,215.
Final Office Action dated Apr. 21, 2017 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (19 pages).
Final Office Action dated Feb. 13, 2015 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (22 pages).
Final Office Action dated Feb. 2, 2005 for U.S. Appl. No. 10/273,386.
Final Office Action dated Jan. 10, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (21 pages).
Final Office Action dated Jan. 29, 2010 for U.S. Appl. No. 11/405,601 (10 pages).
Final Office Action dated Jun. 9, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Final Office Action dated Mar. 2, 2007 for U.S. Appl. No. 10/712,447 (7 pages).
Final Office Action dated Mar. 31, 2006 for U.S. Appl. No. 10/273,386.
Final Office Action dated May 7, 2004 for U.S. Appl. No. 09/896,841 (9 pages).
Final Office Action dated Nov. 15, 2005 for U.S. Appl. No. 10/423,830.
Final Office Action dated Sep. 11, 2008 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Final Office Action issued Apr. 11, 2005 for U.S. Appl. No. 10/187,215.
Final Office Action issued Feb. 2, 2005 for U.S. Appl. No. 10/273,386.
Final Office Action issued Jan. 29, 2010 for U.S. Appl. No. 11/405,601 (10 pages).
Final Office Action issued Mar. 2, 2007 for U.S. Appl. No. 10/712,447 (7 pages).
Final Office Action issued Mar. 31, 2006 for U.S. Appl. No. 10/273,386.
Final Office Action issued May 7, 2004 for U.S. Appl. No. 09/896,841 (9 pages).
Final Office Action issued Nov. 15, 05 for U.S. Appl. No. 10/423,830.
Final Office Action issued on Apr. 21, 2017 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (19 pages).
Final Office Action issued on Feb. 13, 2015 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (22 pages).
Final Office Action issued on Jan. 10, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (21 pages).
Final Office Action issued on Jun. 9, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Final Office Action issued Sep. 11, 2008 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
First Examination Report dated Apr. 8, 2016 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
First Examination Report dated Sep. 18, 2007 for New Zealand Application No. 541504 (2 pages).
First Examination Report issued on Apr. 8, 2016 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
First Examination Report issued Sep. 18, 2007 for New Zealand Application No. 541504 (2 pages).
First Statement of Proposed Amendments filed Sep. 18, 2008 for Australian Application No. 200390825 (13 pages).
Fleisher et al. (1982) Stimulation of arterial endothelial cell prostacyclin synthesis by high density lipoproteins. J Biol Chem. 257:6653-5.
Fogelman et al. (1980) Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci USA. 77:2214-8.
Fogelman, A.M. (2004) When good cholesterol goes bad. Nat Med. 10:902-3.
Folch, J. et al. (1957) A simple method for isolation and purification of total lipides from animal tissues. J Biol Chem. 226:497-509.
Footer et al. (1996) Biochemical evidence that a D-Loop is part of a four-strandedPNA-DNA bundle. Nickel-mediated cleavage of duplex DNA by a Gly-Gly-His-Bis-PNA. Biochemistry. 35(33): 10673-9.
Forte et al. (2002) Altered activities of anti-atherogenic enzymes LCAT, paraoxonase, and platelet-activating factor acetylhydrolase in atherosclerosis susceptible mice. J Lipid Res. 43:477-85.
Fritz, I.B. (1992) What is clusterin? Clin Exp Immunol. 88(3): 375.
Fukuda, et al. (1990) Bilayer forming ion-pair amphi-philes from single chain surfactants. J Am Chem Soc. 112:1635-7.
Further Examination dated Dec. 7, 2016 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Further Examination issued on Dec. 7, 2016 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Futterman, L.G and Lemberg, L. (2004) Statin pleiotropy: fact or fiction? Am J Crit Care. 13(3): 244-9.
Gabay C. and Kushner I. (1999) Acute-phase proteins and other systemic responses to inflammation, N Eng J Med. 340:448-54.
Gambacorti-Passerini et al. (1996) In Vitro Transcription and Translation Inhibition by Anti-PromyelocyticLeukemia (PML)/Retinoic Acid Receptor ά and Anti-PML Peptide Nucleic Acid. Blood. 88(4):1411-7.
Garber et al. (1992) Turnover of synthetic class a amphipathic peptide analogues of exchangeable apolipoproteins in rats. Correlation with physical properties. Arterioscler Thromb. 12(8): 886-94.
Garber et al. (2001) A new synthetic class A amphipathic peptide analogue protects from diet-induced atherosclerosis. J Lipid Res. 42:545-52.
Garber et al. (2001) An Arginine-rich amphipathic helical peptide mediates rapid clearance of plasma cholesterol is dyslipidemic mice. Arterioscler Thromb Vasc Biol. 21:650.
Garber, D.W. et al. (2000) A sensitive and convenient method for lipoprotein profile analysis of individual mouse plasma samples. J Lipid Res. 41:1020-6.
Garber, D.W. et al. (2003) Effect of an arginine-rich amphipathic helical peptide on plasma cholesterol in dyslipidemic mice. Atherosclerosis. 168(2):229-37.
Garber, D.W. et al., Atherosclerosis and Vascular Disease: Effects of Peptide Mimetics of Apolipoproteins. Curr Pharma Biothechnol. 2006; 7(4): 235-40.
Garner et al. (1998) Oxidation of high density lipoproteins. I. Formation of methionine sulfoxide in apolipoproteins AI and AII is an early event that accompanies lipid peroxidation and can be enhanced by alpha-tocopherol. J Biol Chem. 273:6080-7.
Garner et al. (1998) Oxidation of high density lipoproteins. I. Formation of methionine sulfoxide in apolipoproteins Al and All is an early event that accompanies lipid peroxidation and can be enhanced by alpha-tocopherol. J Biol Chem. 273 :6080-7.
Garner et al. (1998) Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residures of apolipoproteins AI and AII. J Biol Chem. 273:6088-95.
Garner et al. (1998) Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residures of apolipoproteins Al and AII. J Biol Chem. 273:6088-95.
Gaut, et al. (2002) Myeloperoxidase produces nitrating oxidants in vivo. J Clin Invest. 109:1311-9.
Geetanjali, B. et al. (2002) Changes in heat shock protein 70 localization and its content in rabbit aorta at various stages of experimental atherosclerosis. Cardiovasc Pathol. 11:97-103.
Gehrs, K.M. et al. (2006) Age-related macular degeneration—emerging pathogenetic and therapeutic concepts. Ann Med. 38(7):450-71.
George et al. (2001) 12/15-lipoxygenase gene disruption attenuates atherogenesis in LDL, receptor-deficient mice. Circulation. 104:1646-50.
Geysen, H.M. et al. (1988) Cognitive features of continuous antigenic determinants. J Mol Recognit. 1(1): 32-41.
Ghersi-Egea et al. (1996) Fate of Cerebrospinal Bluid-Borne Amyloid B-Peptide: Rapid Clearance into Blood and Appreciable Accumulation by Cerebral Arteries, J Neurochem. 67: 880-3.
Gianturco, S. et al. (1982) Receptor-mediated uptake of hypertriglyceridemic very low density lipoproteins by normal human fibroblasts. J Lipid Res. 23: 984-93.
Gianturco, S.H. et al. (1978) Control of 3-hydroxy 3-methylglutaryl CoA reductase activity in cultured human fibroblasts by VLDL of subjects with hypertriglyceredemia. J Clin Invest. 61:320-8.
Gianturco, S.H. et al. (1983) Apolipoprotein E mediates uptake of Sf 100-400 hypertriglyceridemic very low density lipoproteins by the low density lipoprotein receptor pathway in normal human fibroblasts. J Biol Chem. 258:4526-33.
Gillote et al. (1999) Apolipoprotein-mediated plasma membrane microsolubilization. Role of lipid affinity and membrane penetration in the efflux of cellular cholesterol and phospholipid. J Biol Chem. 274(4):2021-8.
Glomset, J.A. (1968) The Plasma lecithin: cholesterol acytransferase reaction. J Lipid Res. 9:155-67.
Goldstein, J.L. et al., Receptor-Mediated Endocytosis: Concepts Emerging from the LDL Receptor System. Ann Rev Cell Biol. 1985; 1:1-39.
Gomez-Foix, A.M. et al. (1992) Adenovirus-mediated Transfer of the Muscle Glycogen Phosphorylase Gene into Hepatocytes Confers Altered Regulation of Glycogen Metabolism. J Biol Chem. 267:25129-34.
Gong et al. (1994) Structural and functional properties of human and mouse apolipoprotein A-I. Biochim. Biophys. Acta. 1213:335-42; Abstract.
Goodman and Gilman, The Pharmacological Basis of Therapeutics, 11th ed., McGraw-Hill Publishing Co. (2005).
Graf, R. and Schachman, H.K. (1996) Random circular permutation of genes and expressed polypeptide chains: application of the method to the catalytic chains of aspartate transcarbamoylase. Proc Natl Acad Sci U S A. 93(21): 11591-6.
Grant of Request for Leave to Amend dated Jul. 3, 2009 for Australian Application No. 200390825 (1 page).
Grant of Request for Leave to Amend issued Jul. 3, 2009 for Australian Application No. 200390825 (1 page).
Greenaway, P.J. et al. (1982) Human cytomegalovirus DNA: BamHI, EcoRI and PstI restriction endonuclease cleavage maps. Gene. 18:355-60.
Greenaway, P.J. et al. (1982) Human cytomegalovirus DNA: BamHI, EcoRI and Pstl restriction endonuclease cleavage maps. Gene. 18:355-60.
Greene et al. Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., Somerset, NJ (1991).
Greten, F.R. et al. (2004) IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 118(3):285-96.
Griendling, K.K. et al. (2000) NAD(P)H Oxidase : Role in Cardiovascular Biology and Disease. Circulation Res. 86:494-501.
Grundy S.M., et al. (2004) Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 110:227-39.
Grundy, S.M., (1998) Hypertriglyceridemia, Atherogenic Dyslipidemia, and the Metabolic Syndrome. Am J Cardiol. 81(4A): 18B-25B.
Grundy, S.M., (1999) Hypertriglyceridemia, Insulin Resistance, and the Metabolic Syndrome. Am J Cardiol. 83(9B): 25F-9F.
Gupta et al. (2004) Calculation of Creatinine Clearance Based on Unadjusted Body Weight Leads to Errors in Renal and Heart Failure Patients. Circulation. 110(7):e70 (2 pages).
Gupta, H. et al. (2005) Apolipoprotein E mimetic Peptide dramatically lowers plasma cholesterol and restores endothelial function in watanabe heritable hyperlipidemic rabbits. Circulation. 111(23): 3112-8.
Gupta, H. et al. (2005) Inhibition of lipopolysaccharide-induced inflammatory responses by an apolipoprotein AI mimetic peptide. Circ Res. 97(3): 236-43.
Gurfinkel et al. (2002) Influenza Vaccine Pilot Study in Acute Coronary Syndromes and Planned Percutaneous Coronary Interventions. The FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study. Circulation. 105:2143-7.
Guzman, R.J. et al. (1993) Efficient Gene Transfer Into Myocardium by Direct Injection of Adenovirus Vectors. Circ Res. 73:1201-7.
Haimovici, R. et al. (2001) The lipid composition of drusen, Bruch's membrane, and sclera by hot stage polarizing light microscopy. Invest Ophthalmol Vis Sci. 42(7): 1592-9.
Haj-Ahmad et al. (1986) Development of a Helper-Independent Human Adenovirus Vectorand Its Use in the Transfer of the Herpes Simplex Virus Thymidine Kinase Gene. J Virology. 57:267-74.
Halcox, J.P. et al. (2002) Prognostic Value of Coronary Vascular Endothelial Dysfunction. Circulation. 106:653-8.
Hamase et al. (2001) Determination of Free D-Proline and D-Leucine in the Brains of Mutant Mice Lacking D-Amino Acid Oxidase Activity. Anal Biochem. 298:253-8.
Handattu et al. (2006) Physical, Chemical, and Structural Studies of Apolipoprotein A-I Mimetics Correlate Well with the Efficacy for Inhibiting Atherosclerosis. Atheroscler Thromb Vasc Biol. 26(5):e64.
Handattu, S.P. et al. (2007) ApoA-I Mimetic Peptides with Differing Ability to Inhibit Atherosclerosis Also Exhibit Differences in Their Interactions with Membrane Bilayers. J Biol Chem. 282:1980-8.
Handattu, S.P. et al. (2013) Two Apolipoprotein E Mimetic Peptides with Similar Cholesterol reducing Properties Exhibit Differential Atheroprotective Effects in LDL-R Null Mice. Atherosclerosis. 227(1):58-64.
Handwerger et al. (1999) Pre-β-HDL stimulates placental lactogen release from human trophoblast cells. Am J Physiol. 276:E384-9.
Hann, M.M., On the Double Bond Isotere of the Peptide Bond: Preparation of an Enkephalin Analogue. J ChemSoc Perkin Trans 1. 1982; 307-14.
Hanvey et al. (1992) Antisense and Antigene properties of Peptide Nucleic Acids. Science. 258(5087): 1481-5.
Harats et al. (2000) Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 20:2100-5.
Hardy et al. (2001) An Automated High-Performance Liquid Chromatography Procedure for the Quantitation of L- and D-Amino Acids by Means of Stepwise Precolumn Derivatization. Anal Biochem. 291:297-9.
Harkin et al. (1997) The Effects of hyper-and hypocarbia on intraparenchymal arterioles in rat brian slices. Neuroreport. 8:1841-4.
Hashimoto (2000) Improvement of intestinal absorption of peptides: absorption of Bi-Phe monoglucosylated insulin to rat intestinal brush-border membrane vesicles. Eur J Pharm Biopharm. 50(2): 197-204.
Hasty, A.H. et al. (1999) Determination of lower threshold of apolipoprotein E resulting in lipoprotein remnant clearance. J Lipid Res. 40:1529-38.
Hauser et al. (1998) Identification of a Receptor Mediating Absorption of Dietary Cholesterol in the Intestine. Biochemistry. 37(51):17843-50.
Havel, R. J. (1985) George Lyman Duff memorial lecture. Role of the liver in atherosclerosis. Arteriosclerosis. 5: 569-80.
Hāyry et al. (1995) Stabile D peptide analog of insulin-like growth factor-1 inhibits smooth muscle cell proliferation after carotid balooning injury in the rat. FASEB J. 9(13): 1336-44.
Heeschen, C. et al., Withdrawal of Statins Increases Event Rates in Patients with Acute Coronary Syndromes. Circulation. 2002; 105(12):1446-52.
Hein, T.W. et al. (2001) Integrin-binding peptides containing RGD produce coronary arteriolar dilation via cyclooxygenase activation. Am J Physiol Heart Circ Physiol. 281(6): H2378-84.
Henriksen et al. (1981) Enhanced macrophage degradation of low density lipoprotein prevously incubated with cultured endolelial cells; recognition by receptor for acetylated low density lipoproteins. Proc Natl Acad Sci USA. 78:6499-503.
Herbert, P. et al., A Large-Scale Process to Produce Microencapsulated Proteins. Pharm Res. 1998; 15(2):357-61.
Hermanowski-Vosatka, A. et al. (2005) 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med. 202(4):517-27.
Hessler et al. (1979) LDL-induced cytotoxicity and its inhibition by 1-DL in human vascular smooth muscle and endothelial cells in culture. Atherosclerosis. 32:213-29 (Abstract).
Hoffman et al. (1997) Isoprostanes: Free Radical-Generated Prostaglandins with constrictor Effects on cerebral Arterioles. Stroke. 28: 844-9.
Holladay, M.W. and D.H. Rich, Synthesis of Hydroxyethylene and Ketomethylene Dipeptide Isoteres. Tetrahedron Lett. 1983; 24(41):4401-4.
Holvoet, P. et al. (1997) β-VLDL Hypercholesterolemia Relative to LDL Hypercholesterolemia is Associated With Higher Levels of Oxidized Lipoproteins and a More Rapid Progression of Coronary Atherosclerosis in Rabbits. Arterioscler Thromb Vasc Biol. 17:2376-82.
Hoogenboom et al. (1992) By-passing immunisation: Human antbodies from synthetic repertoires of germline VH gene segments rearranged in vitro. J Mol Biol. 227:381-8.
Hoogenboom et al. (1992) By-passing immunisation: Human antibodies from synthetic repertoires of germline VH gene segments rearranged in vitro. J Mol Biol. 227:381-8.
Houstis, N. et al. (2006) Reactive Oxygen Species Have a Causal Role in Multiple Forms of Insulin Resistance. Nature. 440: 944-8.
Hristova et al. (1999) An Amphipathic α-Helix at a Membrane Interface: A Structural Study using a Novel X-ray Diffraction Method. J Mol Biol. 290:99-117.
Hruby, V.J., Conformational Restrictions of Biologically Active Peptides via Amino Acid Side Chain Groups. Life Sci. 1982; 31(3):189-99.
Huang and Mahley, Apolipoprotein E. Structure and Function in Lipid Metabolism, Neurobiology, and Alzheimer's Diseases. Neurobiol Dis. 2014; 72PA:3-12.
Huber, M.A. et al. (2004) NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 114(4): 569-81.
Hudson, D. et al., Methionine Enkephalin and Isoteric Analogues I. Synthesis on a Phenolic Resin Support. Int J Pept Prot Res. 1979; 14(3):177-85.
Hussain et al. (2000) High affinity binding between lipoprotein lipase and lipoproteins involves multiple ionic and hydrophobic interactions, does not require enzyme activity, and is modulated by glycosaminoglycans. J Biol Chem. 275: 29324-30.
Hwang, S.J. et al. (1997) Circulating adhesion molecules VCAM-I, ICAM-1, and E-selectin in carotid therosclerosis and incident coronary heart disease cases. The atherosclerosis risk in communities (AMC) study. Circulation. 96:4219-4225.
Hyka et al. (2001) Apolipoprotein A-I Inhibits the Production of Interleukin-10 and Tumor Necrosis Factor-a by Blocking Contact-Mediated Activation of Monocytes by T Lymphocytes. Blood. 97:2381-9.
Hyrup, B. and Nielsen, P.E. (1996) Peptide Nucleic Acids (PNA):Synthesis, Properties and Potential Applications. Bioorg Med Chem. 4(1):5-23.
Internation Preliminary Report on Patentability dated Mar. 2, 2010 by the International Searching Authority for International Patent Application No. PCT/US2008/074470, which was filed on Aug. 27, 2008 and published as WO 2009/032693 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages),
Internation Preliminary Report on Patentability issued on Mar. 2, 2010 by the International Searching Authority for International Patent Application No. PCT/US2008/074470, which was filed on Aug. 27, 2008 and published as WO 2009/032693 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
International Preliminary Examination Report dated Mar. 4, 2003 for PCT App. No. PCT/US01/26457 (5 pages).
International Preliminary Examination Report issued Mar. 4, 2003 for PCT App. No. PCT/US01/26457 (5 pages).
International Preliminary Opinion on Patentability dated Aug. 19, 2010 for PCT App. No. PCT/US2009/033415.
International Preliminary Opinion on Patentability issued Aug. 19, 2010 for PCT App. No. PCT/US2009/033415.
International Preliminary Report on Patentability dated Jan. 31, 2017 by the International Searching Authority for Patent Application No. PCT/US2015/041162, which was filed on Jul. 20, 2015 and published as WO 2016/018665 on Feb. 4, 2016 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation et al.) (6 pages).
International Preliminary Report on Patentability dated Jul. 25, 2011 for International Patent Application No. PCT/US2003/036268.
International Preliminary Report on Patentability dated Mar. 2, 2010 by the International Searching Authority for International Patent Application No. PCT/US2008/074485, which was filed on Aug. 27, 2008 and published as WO 2009/032702 on Mar. 12, 2009 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (9 pages).
International Preliminary Report on Patentability dated Sep. 24, for Patent Application No. PCT/US14/27719, which was filed on Mar. 14, 2014 and published as WO 2014/0152776 on Sep. 25, 2014 (Applicant—UAB Research Foundation//Inventor—Anantharamaiah) (8 pages).
International Preliminary Report on Patentability issued on Jan. 31, 2017 by the International Searching Authority for Patent Application No. PCT/US2015/041162, which was filed on Jul. 20, 2015 and published as WO 2016/018665 on Feb. 4, 2016 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation et al.) (6 pages).
International Preliminary Report on Patentability issued on Jul. 25, 2011 for International Patent Application No. PCT/US2003/036268.
International Preliminary Report on Patentability issued on Mar. 2, 2010 by the International Searching Authority for International Patent Application No. PCT/US2008/074485, which was filed on Aug. 27, 2008 and published as WO 2009/032702 on Mar. 12, 2009 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (9 pages).
International Preliminary Report on Patentability issued on Sep. 24, for Patent Application No. PCT/US14/27719, which was filed on Mar. 14, 2014 and published as WO 2014/0152776 on Sep. 25, 2014 (Applicant—UAB Research Foundation// Inventor—Anantharamaiah) (8 pages).
International Search Report and Written Opinion dated Dec. 15, 2015 by the International Searching Authority for Patent Application No. PCT/US2015/041162, which was filed on Jul. 20, 2015 and published as WO 2016/018665 on Feb. 4, 2016 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation et al.) (11 pages).
International Search Report and Written Opinion dated Jul. 11, 2014 for application PCT/US14/27719, which was filed on Mar. 14, 2014 and published as WO 2014/0152776 on Sep. 25, 2014 (Inventor—Anantharamaiah; Applicant—UAB Research Foundation) (27 pages).
International Search Report and Written Opinion dated Jul. 28, 2009 by the International Searching Authority for International Patent Application No. PCT/US2008/074485, which was filed on Aug. 27, 2008 and published as WO 2009/032702 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (12 pages).
International Search Report and Written Opinion dated Sep. 1, 2009 for PCT App. No. PCT/US2009/033415.
International Search Report and Written Opinion issued on Jul. 11, 2014 for application PCT/US14/27719, which was filed on Mar. 14, 2014 and published as WO 2014/0152776 on Sep. 25, 2014 (Inventor—Anantharamaiah; Applicant—UAB Research Foundation) (27 pages).
International Search Report and Written Opinion issued Sep. 1, 2009 for PCT App. No. PCT/US2009/033415.
International Search Report and Written Opinion mailed on Dec. 15, 2015 by the International Searching Authority for Patent Application No. PCT/US2015/041162, which was filed on Jul. 20, 2015 and published as WO 2016/018665 on Feb. 4, 2016 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation et al.) (11 pages).
International Search Report and Written Opinion mailed on Jul. 28, 2009 by the International Searching Authority for International Patent Application No. PCT/US2008/074485, which was filed on Aug. 27, 2008 and published as WO 2009/032702 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (12 pages).
International Search Report dated May 17, 2002 for PCT App. No. PCT/US01/26457 (3 pages).
International Search Report dated Nov. 17, 2005 for International Patent Application No. PCT/US2003/036268 (4 pages).
International Search Report issued May 17, 2002 for PCT App. No. PCT/US01/26457 (3 pages).
International Search Report issued Nov. 17, 2005 for International Patent Application No. PCT/US2003/036268 (4 pages).
Ishigami, M., et al. (2000) Apolipoprotein E inhibition of vascular smooth muscle cell proliferation but not the inhibition of migration is mediated through activation of inducible nitric oxide synthase. Arteriosc Thromb Vasc Biol. 20:1020-6.
Issue Notification dated Aug. 3, 2016 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Issue Notification dated Dec. 27, 2011 by the U.S. Patent and Trademark Office for U.S. Appl. No. 11/405,601 (1 page).
Issue Notification dated Jul. 1, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Issue Notification dated Oct. 15, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Issue Notification dated Oct. 29, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Issue Notification issued Jul. 1, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Issue Notification issued on Aug. 3, 2016 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Issue Notification issued on Dec. 27, 2011 by the U.S. Patent and Trademark Office for U.S. Appl. No. 11/405,601 (1 page).
Issue Notification issued on Oct. 15, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Issue Notification issued on Oct. 29, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Ito, M.K. et al., Management of Familial Hypercholesterolemias in Adult Patients: Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011; 5(3 Suppl):S38-45.
Jaeger et al. (1989) Improved predictions of secondary structures for RNA. Proc Natl Acad Sci USA. 86:7706-10.
Jakobovits et al. (1993) Analysis of homozygous mutant chimeric mice: Deletion of the immunoglobulin heavy-chain joining region blocks B-cell development and antibody production. Proc Natl Acad Sci USA. 90:2551-5.
Jakobovits et al. (1993) Germ-line transmission and expression of a human-derived yeast artificial chromosome. Nature. 362:255-8.
Jamaluddin et al. (1987) Aggregatory reactions of blood platelets in ustirred dilute suspensions and their monitoring by spectrophotometry. Curr Sci. 56:254-6.
Jamieson et al. (2001) Detection of Lipoprotein(a) in Intraparenchymal Cerebral Vessels: Correlation with Vascular Pathology and Clinical History. Exp Mol Pathol. 71: 99-105.
Jennings-White, C. and R.G. Almquist, Synthesis of Ketomethylene Analogs of Dipeptides. Tetra Lett. 1982; 23(25):2533-4.
Jensen et al. (1997) Kinetics for Hybridization of Peptide Nucleic Acids (PNA) with DNA and RNA Studied with the BIAcore Technique Biochemistry. 36(16):5072-7.
Jin et al. (2003) Inhibition of endothelial lipase causes increased ML cholesterol levels in vivo. J Clin Invest. 111:357-62.
Johnson, J.H. (2006) Trends and Opportunities in the Metabolic Syndrome, Drug Dev Res. 67(7): 539-44.
Johnson, O.L. et al., A Month-Long Effect from a Single Injection of Microencapsulated Human Growth Hormone. Nature Med. 1996; 2(7):795-9.
Jones et al. (1992) Computer Programs to Identify and Classify Amphipathic a Helical Domains. J Lipid Res. 33:287-96.
Jones et al. (1992) Computer Programs to Identify and Classify Amphipathic α Helical Domains. J Lipid Res. 33:287-96.
Jong, M.C. et al. (1996) Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden human apolipoprotein C-I. Arterioscler Thromb Vasc Biol. 16:934-40.
Kabanov et al. (1990) A new class of antivirals: antisense oligonucleotides combined with a hydrophobic substituent effectively inhibit influenza virus reproduction and synthesis of virus-specific proteins in MDCK cells. FEBS Lett. 259: 327-30.
Kaler et al. (1989) Spontaneous vesicle formation in aqueous mixtures of single-tailed surfactants. Science. 245:1371-4.
Kandel ER, Schwartz JH, Jessell TM (Eds.) (1991) Principles of Neural Science, Third Edition. Elsevier: New York, pp. 188-189.
Karle et al. (1998) Crystal structure of the channel-forming polypeptide antiamoebin in a membrane-mimetic environment. Proc Natl Acad Sci USA. 95:5501-4.
Karle et al. (2003) Crystal structure of hydrophobic 19-residue peptide helix containing three centrally located D amino acids. Proc Natl Acad Sci USA. 100(24): 13946-151.
Karle et al. (2004) A combined extented and helical backbone for Boc-(Ala-Leu-Ac7C)2-OME. Peptides Res. 63:174-80.
Kaul, S. et al. (2004) Rapid Reversal of Endothelial Dysfunction in Hypercholesterolemic Apolipoprotein E-Null Mice by Recombinant Apolipoprotein A-IMilano-Phospholipid Complex. J Am Coll Cardiol. 44:1311-9.
Keech, A. et al. (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes (the FIELD study): randomised controlled trial. Lancet. 366: 1849-61.
Kidson, W. et al. (1974) Treatment of Severe Diabetes Mellitus by Insulin Infusion. Br Med J. 2(5921): 691-4.
Kirshenbaum, L.A. et al. (1993) Highly Efficient Gene Transfer into Adult Ventricular Myocytes by Recombinant Adenovirus. J Clin Invest. 92:381-7.
Kissinger, C. et al. (1982) Analysis of Sertoli cell-secreted proteins by two-dimensional gel electrophoresis. Biol Reprod. 27(1): 233-40.
Kita, T. et al. (1981) Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia. Proc Natl Acad Sci USA .78: 2268-72.
Klien, R. et al. (2002) The Association of Atherosclerosis, Vascular Risk Factors, and retinopathy in Adults with Diabetes: The Atherosclerosis Risk in Communities Study. Opthalmology. 109(7): 1225-34.
Knowler, W.C. et al. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 346(6):393-403.
Ko et al. (1993) A. Highdensity lipoprotein reduces epidermal growth factor-induced DNA synthesis in vascular smooth muscle cells. Atherosclerosis, 99: 253-9 (Abstract).
Kockx, et al. (2004) Apolipoprotein A-I-stimulated Apolipoprotein E Secretion from Human Macrophages is Independent of Cholesterol Efflux. J Biol Chem. 279:25966-70.
Koh, K.K., Effects of Statins on Vascular Wall: Vasomotor Function, Inflammation, and Plaque Stability. Cardiovasc Res. 2000; 47(4):648-57.
Kolodgie, F.D. et al. (1996) Hypercholesterolemia in the Rabbit Induced by Feeding Graded Amounts of Low-Level Cholesterol: Methodological Considerations Regarding Individual Variability in Response to Dietary Cholesterol and Development of Lesion Type. Arterioscler Thromb Vasc Biol. 16:1454-64.
Kontos, H.A. and Wei, E.P. (1998) Cerebral arteriolar dilations by KATP channel activators need L-lysine or L-arginine. Am J Physiol. 274 (3 Pt 2): H974-81.
Kowal, R.C. et al. (1989) Low density lipoprotein receptor related protein mediates uptake of cholesteryl ester derived from apolipoprotein E enriched lipoproteins. Proc Natl Acad Sci USA. 86:5810-4.
Kozbor, D. et al. (1982) Human hybridomas constructed with antigen-specific Epstein-Barr virus-transformed cell lines. Proc Natl Acad Sci USA. 79(21): 6651-5.
Kreiger (1999) Charting the Fate of the "Good Cholesterol": Identifcation and Characterization of the High-Density Lipoprotein Receptor Sr—Bi. Ann Rev Biochem. 68: 523-58.
Kullman et al. (1999) Evaluation of the Enantiomeric Composition of Amino Acids in Tobacco. Chirality. 11:669-673.
Kumar et al. (2002) A novel peptide derivative exhibits anti inflammatory and antioxidant activity in adjuvant induced arthritis in rats. Mol Cell Biochem. 229(1-2):9-17.
Kume et al. (1992) Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest. 90:1138-44.
Kwiterovich, P.O. (1998) State-of-the-art update and review: clinical trials of lipid-lowering agents. Am J Cardiol. 82: 3U-7U.
Lalazar, A. et al., Site-Specific Mutagenesis of Human Apolipoprotein E. Receptor Binding Activity of Variants with Single Amino Acd Substitutions. J Biol Chem. 1988; 263(8):3542-5.
Lawrence, M.B. and Springer, T.A. (1991) Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell. 65:859-73.
Le Gal La Salle, G. et al. (1993) An adenovirus vector for gene transfer into neurons and glia in the brain. Science. 259:988-90.
Lee, S. et al. (2001) Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science. 292:2083-6.
Legrand et al. (1992) Molecular Interactions between Human Lactotransferrin and the Phytohemagglutinin-Activated Human Lymphocyte Lactotransferrin Receptor Lie in Two Loop-Containing Regions of the N-Terminal Domain I of Human Lactotransferrin. Biochemistry. 31: 9243-51.
Letsinger et al. (1989) Cholesteryl-conjugated oligonucleotides: Synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture. Proc Natl Acad Sci USA. 86:6553-6.
Letters of Patent dated Sep. 18, 2012 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,514,303, whichwas filed on Jul. 25, 2005 and granted on Sep. 18, 2012 (Inventor Gattadahalli et al.; Applicant—UAB research Foundation) (2 pages).
Letters of Patent issued on Sep. 18, 2012 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,514,303, whichwas filed on Jul. 25, 2005 and granted on Sep. 18, 2012 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (2 pages).
Letters Patent dated Aug. 13, 2009 for New Zealand Application No. 541504 (1 page).
Letters Patent issued Aug. 13, 2009 for New Zealand Application No. 541504 (1 page).
Levine, et al.(1993) In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci USA. 90:12040-4.
Li et al. (1993) An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arteriosc Thromb. 13:197-204.
Li, et al. (2004) Double Belt Structure of Discoidal High Density Lipoproteins: Molecular Basis for Size Heterogeneity. J Mol Biol. 343:1293-311.
Li, J.J. et al., Rebound Phenomenon of Inflammatory Response May Be a Major Mechanism Responsible for Increased Cardiovascular Events After Abrupt Cessation of Statin Therapy. Med Hypotheses. 2006; 66(6):1199-204.
Libby et al. (2002) Inflammation and atherosclerosis. Circulation. 105:1135-43.
Linsel-Nitschke, P. and Tall, A.R. (2005) HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov. 4(3): 193-205.
Mach et al. (1998) Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature. 394:200-3.
Mahley et al. (1999) Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes. J Lipid Res. 40: 1933-49.
Mahley, R. W., Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology. Science. 1988; 240(4852):622-30.
Mahley, R.W. and Z.S. Ji, Remnant Lipoprotein Metabolism: Key Pathways Involving Cell-Surface Heparan Sulfate Proteoglycans and Apolipoprotein E. J Lipid Res. 1999; 40(1):1-16.
Mahley, R.W. et al. (1989) Intravenous infusion of apolipoprotein E accelerates clearance of plasma lipoproteins in rabbits. J Clin Invest. 83: 2125-30.
Manchekar, M. et al. (2004) Apolipoprotein B-Containing Lipoprotein Particle Assembly: Lipid Capacity of the Nascent Lipoprotein Particle. J Biol Chem. 279(38): 39757-66.
Manikandan et al. (2002) Antioxidant potential of a novel tetrapeptide deri-vative in isoproterenol-induced myocardial. Pharmacology. 65:105-9.
Manoharan et al. (1994) Cholic acid-oligonucleotide conjugates for antisense applications. Bioorg Med Chem Lett. 4 1053-60.
Manoharan et al. (1995) Lipidic nucleic acids. Tetrahedron Lett. 36:3651-4.
Marks et al. (1991) By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J Mol Biol. 222:581.
Massie et al. (1986) Construction of a Helper-Free Recombinant Adenovirus That Expresses Polyomavirus Large T Antigen. Mol Cell Biol. 6:2872-83.
Mato et al. (1996) Involvement of specific macrophage-lineage cells surrounding arterioles in barrier and scavenger function in brain cortex. Proc Natl Acad Sci USA. 93: 3269-74.
Mazoyer, E. et al. (1990) KRDS, a new peptide derived from human lactotransferrin, inhibits platelet aggregation and release reaction. Eur J Biochem. 194:43-9.
McGarry, J.D. (2002) Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 51(1):7-18.
Meera et al. (1999) Inhibition of neutrophil derived lysosomal enzymes and reactive oxygen species by a novel tetrapeptide. Inflamm Res. 48(9):479-84.
Mehrabian et al. (2002) Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 91:120-6.
Mendez et al. (1994) Synthetic Amphipathic Helical Peptides that Mimic Apolipoprotein A-I in Clearing Cellular Cholesterol. J Clin Invest. 94: 1698-705.
Merrifield et al. (1995) Retro and Retroenantio Analogs of Cecropin-Melittin Hybrids. Proc Natl Acad Sci USA. 92: 3449-53.
Mertens, A. et al. (2003) Increased Low-Density Lipoprotein Oxidation and Impaired High-Density Lipoprotein Antioxidant Defense are Associated With Increased Macrophage Homing and Atherosclerosis in Dyslipidemic Obese Mice: LCAT Gene Transfer Decreases Atherosclerosis. Circulation. 107:1640-6.
Miller, A.D. and Buttimore, C. (1986) Redesign of Retrovirus Packaging Cell Lines To Avoid Recombination Leading to Helper Virus Production. Mol Cell Biol. 6: 2895.
Miller, A.D. and Buttimore, C. (1986) Redesign of Retrovirus Packaging Cell Lines to Avoid.
Mims, M. P. et al. (1994) A Nonexchangeable Apolipoprotein E Peptide That Mediates Binding to the Low Density Lipoprotein Receptor. J. Biol. Chem. 269: 20539-647.
Miscellaneous Action dated Oct. 24, 2008 for U.S. Appl. No. 11/405,601 (2 pages).
Miscellaneous Action issued Oct. 24, 2008 for U.S. Appl. No. 11/405,601 (2 pages).
Mishra et al. (1994) Interaction of Synthetic Peptide Analogs of the Class A Amphipathic Helix with Lipids: Evidence for the Snorkel Hypothesis. J Biol Chem. 269: 7185-91.
Mishra et al. (1995) Effect of the Arrangement of Tandem Repeating Units of Class A Amphipathic α-Helixes on Lipid Interaction. J Biol Chem. 270:1602-11.
Mishra et al. (1996) Interaction of Model Class A1, Class A2, and Class Y Amphipathic Helical Peptides with Membranes. Biochemistry. 35:11210-20.
Mishra et al. (1998) Studies of Synthetic Peptides of Human Apolipoprotein A-I Containing Tandem Amphipathic α-Helixes. Biochemistry. 37: 10313-24.
Mishra et al. (2001) Solution NMR structure of a model class A (apolipoprotein) amphipathic a helical peptide. Peptides. 22:567-73.
Mishra et al. (2001) Solution NMR structure of a model class A (apolipoprotein) amphipathic α helical peptide. Peptides. 22:567-73.
Mishra et al. (2006) Association of a model class A (apolipoprotein) amphipathic a helical peptide with lipid: high resolution NMR studies of peptide lipid discoidal complexes. J Biol Chem. 281:6511-9.
Mishra et al. (2006) Association of a model class A (apolipoprotein) amphipathic α helical peptide with lipid: high resolution NMR studies of peptide lipid discoidal complexes. J Biol Chem. 281:6511-9.
Miyazaki et al. (1995) Intravenous Injection of Rabbit Apolipoprotein A-I Inhibits the Progression of Atherosclerosis in Cholesterol-Fed Rabbits. Arterioscler Thromb Vasc Biol. 15:1882-8.
Moller, D.E. and K.D. Kaufman (2005) Metabolic Syndrome: A Clinical and Molecular Perspective. Ann Rev Med. 56: 25-62.
Moore, D.J. et al. (1995) Age-related variation in the hydraulic conductivity of Bruch's membrane. Invest Ophthalmol Vis Sci. 36(7): 1290-7.
Morley, J.S., Modulation of the Action of Regulatory Peptides by Structural Modification. Trends Pharm Sci. 1(2):463-8 (1980) (general review).
Morrison et al. (1984) Chimeric human antibody molecules: Mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci USA. 81:6851-5.
Morsy et al. (1993) Efficient Adenoviral-mediated Ornithine Transcarbamylase Expression in Deficient Mouse and Human Hepatocytes. J Clin Invest. 92:1580-6.
Moullier et al. (1993) Correction of lysosomal storage in the liver and spleen of MPS VII mice by implantation of genetically madified skin fibroblast. NatGenet. 4:154-9.
Mulder et al. (2004) Low-density lipoprotein receptor-knockout mice display impaired spatial memory associated with a decreased synaptic density in the hippocampus. Neurobiol Disease. 16: 212-9.
Mulligan, R.C. (1993) The basic science of gene therapy. Science. 260:926-32.
Murugesan et al. (1994) High-density lipoprotein stimulates endothelial cell movement by a mechanism distinct from basic fibroblast growth factor. Circ Res. 74: 1149-56.
Nag et al. (1997) Cerebrovascular Changes in Chronic Hypertension Protective Effects of Enalapril in Rats. Stroke. 28: 1028-34.
Nagata et al. (1994) Distribution of free D-serine in vertebrate brains. Brain Res. 634: 291-5.
Nagata et al. (1995) Free D-serine concentration in normai and Alzheimer human brain. Brain Res Bull. 38(2): 181-3.
Nagata et al. (2002) Hemodynamic Aspects of Alzheimer's Disease. Ann N Acad Sci. 977: 391-402.
Naghavi, M. et al. (2003) Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice. Circulation. 107(5): 762-8.
Nakamura et al. (1997) Deposition of amyloid β protein (Aβ)subtypes [Aβ40 and Aβ42(43)] in canine senile plaques and cerebral amyoloid angiopathy. Acta Neuropathol. 94: 323-8.
Nanjee et al. (1999) Acute effects of intravenous infusion of apoA-Uphosphos-phatidycholine discs on plasma lipoproteins in humans. Arterioscler Thromb Vase Biol. 19:979-89.
Nanjee et al. (2001) Intravenous apoA-1/lecithin discs increase pre-β-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J Lipid Res. 42:1586-93.
Navab et al. (1991) Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest. 88:2039-46.
Navab et al. (1997) Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest. 99:2005-19.
Navab et al. (2000) Normal high density lipoprotein inhibits three steps in the formation of midly oxidized low density lipoprotein: step 1. J Lipid Res. 41:1481-94.
Navab et al. (2000) Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res. 41:1495-508.
Navab et al. (2001) A cell-free assay for detecting HDL that is dysfunctional in preventing the formation of or inactivating oxidized phospholipids. J Lipid Res 2001; 42:1308-17.
Navab et al. (2001) HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Bio.21:481-8.
Navab et al. (2003) Oral synthetic phospholipids (DMPC) raises high-density lipoprotein cholesterol levels, improves high-density lipoprotein function, and markedly reduces atherosclerosis in apolipoprotein E-null mice. Circulation. 108:1735-9.
Navab et al. (2004) Oral D-4F causes formation of pre-β high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apo;ipoprotin E-null mice. Circulation. 109:3215-20.
Navab et al. (2004) The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and L. J Lipid Res. 45: 993-1007.
Navab et al. (2005) An Apolipoprotein A-I Mimetic Works Best in the Presence of Apolipoprotein A-I. Circ. Res. 97:1085-6.
Navab et al. (2005) An oral ApoJ peptide renders HDL anti-inflammatory in Mice and Monkeys and dramatically reduces atherosclerosis in Apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 25:1932-7.
Navab et al. (2005) Apolipoprotein A-I Mimetic Peptides. Arterioscler Thromb Vasc Biol. 25:1325-31.
Navab et al. (2005) D-4F and Statins Synergize to Render HDL Antiinflammatory in Mice and Monkeys and Cause Lesion Regression in Old Apolipoprotein E-Null Mice. Arterioscler Thromb Vasc Biol. 25:1426-32.
Navab et al. (2005) Oral Small Peptides render HDL antiinflammatory in mice, and monkeys and reduce atherosclerosis in ApoE null mice. Circ Res. 97:524-32.
Navab et al. (2005) The double jeopardy of HDL. Ann Med 37(3):173-8.
Navab et al. (2005) The Role of High-Density Lipoprotein in Inflammation. Cardiovasc Med.15:158-61.
Navab et al., A Novel Method for Oral Delivery of Apolipoprotein Mimetic Peptides Synthesized from All L-Amino Acids. J Lipid Res. 2009; 50(8):1538-47.
Navab M, et al. (2002) Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 105(3): 290-2.
Navab, M. et al. (2004) Apparent Paradox of Low-Fat "Healthy" Diets Increasing Plasma Levels of Oxidized Low-Density Lipoprotein and Lipoprotein(a). Arterioscler Thromb Vasc Biol. 24:392-3.
Nguyen et al. (2006) Apolipoprotein A-I-mimetic peptides with antioxidant actions. Arch Biochem Biophys. 451:34-42.
Nicholls, S.J. et al. (2005) Formation of Dysfunctional High-Density Lipoprotein by Myeloperoxidase. Trends Cardiovasc Med. 15(6): 212-9.
Nicholls, S.J. et al. (2006) Relationship Between Atheroma Regression and Change in Lumen Size After Infusion of Apolipoprotein A-I Milano. J Am Coll Cardiol. 47(5):992-7.
Nielsen et al. (1991) Sequence-Selective Recognition of DNA by Strand Displacement with a Thymine-Substituted Polyamide. Science. 254:1497-500.
Nievelstein et al. (1991) Lipid accumulation in rabbit aortic intima two hours after bolus infusion of low density lipoprotein: A deep-etch and immuno-localization study of ultra-rapidly frozen tissue. Arterioscler Thromb. 11: 1795-805.
Nikoulin, I.R. et al. (1998) An Apolipoprotein E Synthetic Peptide Targets to Lipoproteins in Plasma and Mediates Both Cellular Lipoprotein Interactions in Vitro and Acute Clearance of Cholesterol-rich Lipoproteins in Vivo. J Clin Invest. 101(1): 223-34.
Nirmala et al. (1999) Curcumin treatment modulates collagen metabolism in isoproterenol induced myocardial necrosis in rats. Mol Cell Bioche. 197(1-2):31-7.
Nirmala, C. and Puvanakrishnan, R. (1996) Effect of curcumin on certain lysosomal hydrolases in isoproterenol-induced myocardial infarction in rats. Biochem Pharmacol. 51(1):47-51.
Nissen, S.E. et al., Effect of Recombinant ApoA-1 Milano on Coronary Atherosclerosis in Patients with Acute Coronary Syndromes: a Randomized Controlled Trial. JAMA. 2003; 290(17):2292-300.
Nofer, J.R. et al. (2004) HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest. 113:569-81.
Nomoto et al. (1998) Improvement of Intestinal Absorption of Peptide Drugs by Glycosylation: Transport of Tetrapeptide by the Sodium Ion-Dependent D-Glucose Transporter. J Phar Sci. 87(3):326-32.
Non Final Rejection dated Sep. 20, 2019 by the USPTO for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 A1 on Jan. 7, 2016 (Inventor—Gattadahalli M. Anantharamaiah, et al.) (6 pages).
Non Final Rejection was issued on Sep. 20, 2019 by the USPTO for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 A1 on Jan. 7, 2016 (Inventor—Gattadahalli M. Anantharamaiah, et al.) (6pages).
Non-Final Office Action dated Apr. 18, 2005 for U.S. Appl. No. 10/423,830.
Non-Final Office Action dated Aug. 21, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, filed Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (23 pages).
Non-Final Office Action dated Aug. 26, 2004 for U.S. Appl. No. 10/187,215 (7 pages).
Non-Final Office Action dated Jan. 13, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (15 pages).
Non-Final Office Action dated Jan. 17, 2008 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Non-Final Office Action dated Jan. 22, 2003 for U.S. Appl. No. 09/645,454.
Non-Final Office Action dated Jan. 8, 2004 for U.S. Appl. No. 10/187,215 (15 pages).
Non-Final Office Action dated Jul. 10, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (26 pages).
Non-Final Office Action dated Jul. 15, 2014 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,080, filed Apr. 21,2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (21 pages).
Non-Final Office Action dated Jul. 6, 2016 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (20 pages).
Non-Final Office Action dated Jun. 10, 2009 for U.S. Appl. No. 11/405,601 (14 pages).
Non-Final Office Action dated Jun. 13, 2008 for U.S. Appl. No. 10/712,447 (8 pages).
Non-Final Office Action dated Jun. 14, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiahet al.; Applicant—UAB research Foundation) (11 pages).
Non-Final Office Action dated Jun. 21, 2004 for U.S. App. No. 10/273,386.
Non-Final Office Action dated Jun. 29, 2012 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applican—UAB Research Foundation) (13 pages).
Non-Final Office Action dated Mar. 12, 2018 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant-UAB Research Foundation) (18 pages).
Non-Final Office Action dated May 27, 2011 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Non-Final Office Action dated May 31, 2006 for U.S. Appl. No. 10/712,447 (11 pages).
Non-Final Office Action dated Nov. 1, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Non-Final Office Action dated Nov. 19, 2007 for U.S. Appl. No. 10/712,447 (9 pages).
Non-Final Office Action dated Oct. 16, 2017 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant-UAB Research Foundation) (12 pages).
Non-Final Office Action dated Oct. 2, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Non-Final Office Action dated Oct. 21, 2003 for U.S. Appl. No. 09/896,841 (12 pages).
Non-Final Office Action dated Oct. 28, 2005 for U.S. Appl. No. 10/187,215.
Non-Final Office Action dated Sep. 7, 2005 for U.S. Appl. No. 10/273,386.
Non-Final Office Action issued Apr. 18, 2005 for U.S. Appl. No. 10/423,830.
Non-Final Office Action issued Aug. 26, 2004 for U.S. Appl. No. 10/187,215 (7 pages).
Non-Final Office Action issued Jan. 17, 2008 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Non-Final Office Action issued Jan. 22, 2003 for U.S. Appl. No. 09/645,454.
Non-Final Office Action issued Jan. 8, 2004 for U.S. Appl. No. 10/187,215 (15 pages).
Non-Final Office Action issued Jun. 10, 2009 for U.S. Appl. No. (14 pages).
Non-Final Office Action issued Jun. 13, 2008 for U.S. Appl. No. 10/712,447 (8 pages).
Non-Final Office Action issued Jun. 21, 2004 for U.S. Appl. No. 10/273,386.
Non-Final Office Action issued May 31, 2006 for U.S. Appl. No. 10/712,447 (11 pages).
Non-Final Office Action issued Nov. 19, 2007 for U.S. Appl. No. 10/712,447 (9 pages).
Non-Final Office Action issued Oct. 21, 2003 for U.S. Appl. No. 09/896,841 (12 pages).
Non-Final Office Action issued Oct. 28, 2005 for U.S. Appl. No. 10/187,215.
Non-Final Office Action issued on Aug. 21, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, which was filed on Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (23 pages).
Non-Final Office Action issued on Jan. 13, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (15 pages).
Non-Final Office Action issued on Jul. 10, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (26 pages).
Non-Final Office Action issued on Jul. 15, 2014 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (21 pages).
Non-Final Office Action issued on Jul. 6, 2016 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (20 pages).
Non-Final Office Action issued on Jun. 14, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiahet al .; Applicant—UAB research Foundation) (11 pages).
Non-Final Office Action issued on Jun. 29, 2012 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (13 pages).
Non-Final Office Action issued on Mar. 12, 2018 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, which was filed on Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (18 pages).
Non-Final Office Action issued on May 27, 2011 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728,filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Non-Final Office Action issued on Nov. 1, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Non-Final Office Action issued on Oct. 16, 2017 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (12 pages).
Non-Final Office Action issued on Oct. 2, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Non-Final Office Action issued Sep. 7, 2005 for U.S. Appl. No. 10/273,386.
Norton et al. (1995) Targeting Peptide Nucleic Acid-Protein Conjugates to Structural Features Within Duplex DNA. Bioorg Med Chem. 3(4):437-45.
Notice of Abandonment dated Mar. 12, 2014 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, filed Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (2 pages).
Notice of Abandonment dated May 13, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Notice of Abandonment dated May 21, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Notice of Abandonment issued on Mar. 12, 2014 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, which was filed on Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (2 pages).
Notice of Abandonment issued on May 13, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Notice of Abandonment issued on May 21, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Notice of Acceptance dated Apr. 10, 2017 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Notice of Acceptance dated Apr. 11, 2017 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Notice of Acceptance dated Oct. 14, 2008 for Australian Application No. 200390825 (3 pages).
Notice of Acceptance issued Oct. 14, 2008 for Australian Application No. 200390825 (3 pages).
Notice of Acceptance issued on Apr. 10, 2017 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Notice of Acceptance issued on Apr. 11, 2017 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Notice of Allowability issued on Jul. 22, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Notice of Allowability issued on Jul. 22, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Notice of Allowance dated Apr. 21, 2016 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Notice of Allowance dated Aug. 20, 2006 for U.S. Appl. No. 10/273,386.
Notice of Allowance dated Aug. 3, 2015 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Notice of Allowance dated Dec. 10, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Notice of Allowance dated Dec. 17, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Notice of Allowance dated Dec. 2, 2009 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Notice of Allowance dated Dec. 20, 2004 for U.S. Appl. No. 09/896,841 (5 pages).
Notice of Allowance dated Feb. 12, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (2 pages).
Notice of Allowance dated Feb. 24, 2012 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,514,303, whichwas filed on Jul. 25, 2005 and granted on Sep. 18, 2012 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (1 page).
Notice of Allowance dated Feb. 3, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (10 pages).
Notice of Allowance dated Jan. 29, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (2 pages).
Notice of Allowance dated Jun. 25, 2003 for U.S. Appl. No. 09/645,454.
Notice of Allowance dated May 1, 2006 for U.S. Appl. No. 10/187,215.
Notice of Allowance dated Nov. 21, 2006 for U.S. Appl. No. 10/423,830.
Notice of Allowance dated Sep. 9, 2011 for U.S. Appl. No. 11/405,601 (5 pages).
Notice of Allowance issued Aug. 20, 2006 for U.S. Appl. No. 10/273,386.
Notice of Allowance issued Dec. 2, 2009 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Notice of Allowance issued Dec. 20, 2004 for U.S. Appl. No. 09/896,841 (5 pages).
Notice of Allowance issued Jun. 25, 2003 for U.S. Appl. No. 09/645,454.
Notice of Allowance issued May 1, 2006 for U.S. Appl. No. 10/187,215.
Notice of Allowance issued Nov. 21, 2006 for U.S. Appl. No. 10/423,830.
Notice of Allowance issued on Apr. 21, 2016 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Notice of Allowance issued on Aug. 3, 2015 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Notice of Allowance issued on Dec. 10, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Notice of Allowance issued on Dec. 17, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Notice of Allowance issued on Feb. 12, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (2 pages).
Notice of Allowance issued on Feb. 24, 2012 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,514,303, whichwas filed on Jul. 25, 2005 and granted on Sep. 18, 2012 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (1 page).
Notice of Allowance issued on Feb. 3, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (10 pages).
Notice of Allowance issued on Jan. 29, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (2 pages).
Notice of Allowance issued on Jul. 9, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Notice of Allowance issued on Jul. 9, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and granted as 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Notice of Allowance issued Sep. 9, 2011 for U.S. Appl. No. 11/405,601 (5 pages).
Notice of Allowance with Interview Summary and Examiner's Amendment dated Feb. 24, 2009 for U.S. Appl. No. 10/712,447 (7 pages).
Notice of Allowance with Interview Summary and Examiner's Amendment issued Feb. 24, 2009 for U.S. Appl. No. 10/712,447 (7 pages).
Nuttall, M.E. an Gimble, J.M. (2000) Is there a therapeutic opportunity to either prevent or treat osteopenic disorders by inhibiting marrow adipogenesis? Bone. 27(2):177-84.
Oberhauser et al. (1992) Effective incorporation of 2′-O-methyl-oligoribonucleotides into liposomes and enhanced cell association through modification with thiocholesterol. Nucl Acids Res. 20(3):533-8.
O'Brien et al. (1996) Neovascular expression of E-selectin, inter-cellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation. 93:672-82.
Obunike, J.C. et al. (2000) The heparin-binding proteins apolipoprotein E and lipoprotein lipase enhance cellular proteoglycan production. Arterioscler Thromb Vasc Biol. 20:111-8.
O'Connell, B.J. and Genest, J., Jr. (2001) High-density lipoproteins and endothelial function. Circulation. 104:1978-83.
Office Action dated Apr. 25, 2016 by the Canadian Intellectual Poperty Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action dated Aug. 10, 2009 for Canadian Application No. 2,514,303 (3 pages).
Office Action dated Dec. 11, 2017 by the Patent Office of Japan for Patent Application No. 2016-502527, which was filed on Mar. 14, 2014 and published as 2016-515137 on May 26, 2017 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (Original-4 pages // Translation—6 pages).
Office Action dated Feb. 1, 2018 by the European Patent Office for Patent Application No. 14769489.7, which was filed on Mar. 14, 2014 and published as EP 2996706 on Mar. 22, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Office Action dated Feb. 3, 2015 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action dated Jan. 23, 2015 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,714,082, which was filed Aug. 4, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Office Action dated Jul. 23, 2013 by the Patent Office of Japan for Japanese Patent Application No. 2010-523116, which was filed on Feb. 26, 2010 and published as 2010-537638 on Dec. 9, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (13 pages).
Office Action dated Jul. 3, 2018 by the Canadian Intellectual Property Office for Patent Application No. 2,704,729, which was filed on Feb. 25, 2010 (Inventor Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Office Action dated May 6, 2017 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action dated Oct. 6, 2010 for Canadian Application No. 2,514,303 (2 pages).
Office Action dated Sep. 28, 2018 by the Intellectual Property Office of India for Patent Application No. 6250/CHENP/2015, which was filed on Oct. 9, 2015 and published on Jul. 1, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Office Action issued Aug. 10, 2009 for Canadian Application No. 2,514,303 (3 pages).
Office Action issued Oct. 6, 2010 for Canadian Application No. 2,514,303 (2 pages).
Office Action issued on Apr. 25, 2016 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action issued on Dec. 11, 2017 by the Patent Office of Japan for Patent Application No. 2016-502527, which was filed on Mar. 14, 2014 and published as 2016-515137 on May 26, 2017 (Inventor—G.M. Anantharamaiah, et al.; Applican—UAB Research Foundation) (Origina—4 pages // Translation—6 pages).
Office Action issued on Feb. 1, 2018 by the European Patent Office for Patent Application No. 14769489.7, which was filed on Mar. 14, 2014 and published as EP 2996706 on Mar. 22, 2016 (Inventor—Anantharamaiah et al.; Applican—UAB Research Foundation) (5 pages).
Office Action issued on Feb. 3, 2015 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action issued on Jan. 23, 2015 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,714,082, which was filed on Aug. 4, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Office Action issued on Jul. 3, 2018 by the Canadian Intellectual Property Office for Patent Application No. 2,704,729, which was filed on Feb. 25, 2010 (Inventor Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Office Action issued on May 6, 2017 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action issued on Sep. 28, 2018 by the Intellectual Property Office of India for Patent Application No. 6250/CHENP/2015, which was filed on Oct. 9, 2015 and published on Jul. 1, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Office Action mailed on Jul. 23, 2013 by the Patent Office of Japan for Japanese Patent Application No. 2010-523116, which was filed on Feb. 26, 2010 and published as 2010- 537638 on Dec. 9, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Founadtion) (13 pages).
Office Action was dated Jun. 26, 2019 by the Canadian Patent Office for CA Application No. 2954475, which was filed on Jul. 20, 2015 and published as CA 2954475 Al on Feb. 4, 2016 (Applicant—UAB Research Foundation, et al.) (4 pages).
Office Action was dated Oct. 7, 2019 by the Canadian Patent Office for Canadian Application No. 2903869, filed on Mar. 14, 2014 (Applicant—U.A.B. Research Foundation, et al) (5 Pages).
Office Action was issued on Jun. 26, 2019 by the Canadian Patent Office for CA Application No. 2954475, which was filed on Jul. 20, 2015 and published as CA 2954475 A1 on Feb. 4, 2016 (Applicant—UAB Research Foundation, et al.) (4 pages).
Office Action was issued on Oct. 7, 2019 by the Canadian Patent Office for Candian Application No. 2903869, filed on Mar. 14, 2014 (Applicant—U.A.B. Research Foundation, et al.) (5 Pages).
Oguchi et al. (2000) Monoclonal antibody against vascular cell adhesion molecule-1 inhibits neointimal formation after periadventitial carotid artery injury in genetically hypercholesterolemic mice. Arterioscler Thromb Vasc Biol. 20:1729-36.
Oram and Yokoyama (1996) Apolipoprotein mediated removal of cellular cholesterol and phospholipids. J Lipid Res. 37: 2473-91.
Oram, J.F. and J.W. Heinecke, ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter that Protects Against cardiovascular Disease. Physiol Rev. 2005; 85(4): 1343-72.
Otvos, J.D. et al. (2006) Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 113(12):1556-63.
Ou et al. (2003) AP-4F, antennapedia peptide linked to an amphipathic a helical peptide, increases the efficiency of lipofectamine-mediated gene transfection in endothelial cells. Biochem Biophys Res Commun. 305:605-10.
Ou et al. (2003) L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemic and sickle cell disease. Circulation. 107:2337-41.
Ou et al. (2003) L-4F, an apolipoprotein A-I mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells. Circulation. 107:1520-4.
Ou et al. (2005) Effects of D-4F on Vasodilation and Vessel Wall Thickness in Hyperholesterolemic LDL Receptor—Null and LDL Receptor/Apolipoprotein A-I Double-Knockout Mice on Western Diet. Circ Res. 97:1190-7.
Owens, B.J. et al. (1990) Apolipoprotein A-I and its amphipathic helix peptide analogues inhibit human immunodeficiency virus-induced syncytium formation. J Clin Invest. 86(4): 1142-50.
Paigen et al. (1990) Atherosclerosis Susceptibility Differences among Progenitors of Recombinant Inbred Strains of Mice. Arteriosclerosis. 10: 316-23.
Paka et al. (1999) Apolipoprotein E Containing High Density Lipoprotein Stimulates Endothelial Production of Heparan Sulfate Rich in Biologically Active Heparin-like Domains. J Biol Chem. 274:4816-23.
Palgunachari, M.N. et al., Only the Two End Helixes of Eight Tandem Amphipathic Helical Domains of Human Apo A-I Have Significant Lipid Affinity. Implications for HDL Assembly. Arteriosclerosis, Thromb Vasc Biol. 1996; 16(2):328-38 (27 pages).
Palinski et al. (1994) ApoE-Deficient Mice are a Model of Lipo-protein Oxidation in Atherogenesis: Demonstration of Oxidation-Specific Epitopes in Lesions and High Titers of Autoantibodies to Malondialdehyde-Lysine in Serum. Arterioscler Thromb. 14(4):605-16.
Pan, T.C. et al. (1987) Rabbit apolipoprotein A-I mRNA and gene: Evidence that rabbit apolipoprotein A-I is synthesized in the intestine but not in the liver. Eur J Biochem. 30:99-104.
Panizzutti et al. (2001) A New Strategy to Decrease N-methyl-D-aspartate (NMDA) Receptor Coactivation: Inhibition of D-serine Synthesis by Converting Serine Racemase into an Eliminase. Proc Natl Acad Sci USA. 98:5294-9.
Papo et al. (2002) The consequence of sequence alteration of an amphipathic α-helical antimicrobial peptide and its diastereomers. J Biol Chem. 277(37):33913-21.
Pappenheimer et al. (1994) Intestinal Absorption and Excretion of Octapeptides Composed of D Amino Acids. Proc Nail Acad Sci USA. 91:1942-5.
Pappenheimer et al. (1997) Absorption and Excretion of Undegradable Peptides: Rols of Lipid Solubility and Net Charge. J Pharmacol Exp Ther. 280(1):292-300.
Pardridge et al. (1995) Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo. Proc Natl Acad Sci USA. 92(12):5592-6.
Parhami, F. et al. (1997) Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol. 17(4): 680-7.
Pasceri et al. (2000) Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 102:2165-8.
Pasceri et al. (2001) Modulation of Creactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs, Circulation. 103:2531-4.
Pasqui, A.L. et al. (2005) Structural and functional abnormality of systemic microvessels in cardiac syndrome X. Nutr Metab Cardiovasc Dis. 15(1): 56-64.
Pastan et al. (1988) A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc Natl Acad Sci USA. 85: 4486.
Pászty et al. (1994) Apolipoprotein Al Transgene Corrects Apolipoprotein E Deficiency-induced Atherosclerosis in Mice. J Clin Invest. 94:899-903.
Patent Examination Report No. 1 dated Apr. 15, 2016 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Patent Examination Report No. 1 issued on Apr. 15, 2016 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Pillot et al. (1997) The 118-135 peptide of the human prion protein forms amloid fibrils and induces liposome fusion. J Mol Biol. 274: 381-93.
Pilone (2000) D-amino acid oxidase: new findings. Cell Mol Life Sci. 57:1732-47.
Plump et al. (1994) Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses stherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci USA. 91:9607-11.
Pohle, K. et al. (2001) Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation. 104(16): 1927-32.
Posttranslational Covalent Modification of Proteins, B.C. Johnson, Ed., Academic Press, New York, pp. 1-12 (1983).
Preliminary Amendment filed Mar. 12, 2010 filed with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (8 pages).
Preliminary Amendment filed May 14, 2004 for U.S. Appl. No. 10/712,447 (7 pages).
Preliminary Amendment filed Nov. 13, 2003 for U.S. Appl. No. 10/712,447 (6 pages).
Preliminary Amendment filed on Aug. 25, 2015 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Preliminary Amendment filed on Jul. 14, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Preliminary Amendment filed on Jul. 14, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Preliminary Amendment filed on Jul. 6, 2010 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Preliminary Amendment filed on Jul. 6, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Preliminary Amendment filed on Jul. 6, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Preliminary Amendment filed on Mar. 16, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Preliminary Amendment filed on Mar. 16, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Preliminary Amendment filed on Sep. 11, 2015 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al; Applicant-UAB Research Foundation) (3 pages).
Presta (1992) Antibody engineering. Curr Opin Struct Biol. 2:593-6. Purdue News (2000) ‘Microspheres’ Offer Promise for Oral Drug Delivery (pp. 1-3).
Presta (1992) Antibody engineering. Curr Opin Struct Biol. 2:593-6.
Purdue News (1997) New Oral Insulin Delivery System Shows Promise (pp. 1-3).
Purdue News (2000) ‘Microspheres’ Offer Promise for Oral Drug Delivery (pp. 1-3).
Purdue News (2000) ‘Migrosphergs’ Offer Promise for Oral Drug Delivery (pp. 1-3).
Quyyumi, A.A. (1998) Endothelial Function in Health and Disease: New Insights into the Genesis of Cardiovascular Disease. Am J Med. 105:32S-9S.
Rader, D.J. (2003) Regulation of Reverse Cholesterol Transport and Clinical Implications. Am J Cardiol. 92:42J-9J.
Ragot, T. et al. (1993) Replication-defective recombinant adenovirus expressing the Epstein-Barr virus (EBV) envelope glycoprotein gp340]220 induces protective immunity against EBV-induced lymphomas in the cottontop tamarin. J Gen Virol. 74:501-7.
Raha et al. (1988) KRDS a tetra peptide derived from lactotransferrin inhibits binding of monoclonal antibody against glycoprotein Iib-IIIa on ADP-stimulated platelets and megakaryocytes. Blood. 72: 172-8.
Raha et al. (1988) KRDS a tetra peptide derived from lactotransferrin inhibits binding of monoclonal antibody against glycoprotein lib-llla on ADP-stimulated platelets and megakaryocytes. Blood. 72: 172-8.
Raj arathnam et al. (1994) 1H NMR studies of interleukin 8 analogs: characterization of the domains essential for function. Biochemistry. 33:6623-30.
Rajashree, S. and Puvanakrishnan, R. (1996) Alterations in certain lysosomal glycohydrolases and cathepsins in rats on dexamethasone administration. Mol Cell Biochem. 154(2):165-70.
Rajashree, S. and Puvanakrishnan, R. (1998) Dexamethasone induced alterations in enzymatic and nonenzymatic antioxidant status in heart and kidney of rats. Mol Cell Biochem. 181(1-2):77-85.
Rajashree, S. and Puvanakrishnan, R. (1999) Dexamethasone induced alterations in the levels of proteases involved in blood pressure homeostasis and blood coagulation in rats. Mol Cell Biochem. 197(1-2):203-8.
Rall, S. C., Jr. et al., Structural basis for Receptor Binding Heterogeneity of Apolipoprotein E from Type III Hyperlipoproteinemic Subjects. Proc Natl Acad Sci USA. 1982; 79(15):4696-700.
Ram et al. (1993) In Situ Retroviral-mediated Gene Transfer for the Treatment of Brain Tumors in Rats. Cancer Res. 53:83-8.
Ramesh et al. (1998) A novel surface-active peptide derivative exhibits in vitro inhibition of platelet aggregation. Peptides. 19:1695-702.
Ramesh et al. (1998) Effect of a novel tetrapeptide derivative in a model of isoproterenol induced myocardial necrosis. Mol Cell Biochem. 187(1-2):173-82.
Ramprasad et al. (2002) Sustained-delivery of an apolipoproteinE—peptidomimetic using multivesicular liposomes lowers serum cholesterol levels. J Controlled Release. 79:207-18.
Ranganathan, D. et al. (2000) Channel-Forming Self-Assembling, Bishelical Amphiphilic Peptides: Design, Synthesis and Crystal Structure of Py (Aibn)2, n=2, 3, 4. J Peptide Res. 56(6): 416-26.
Rapp, J.H. et al. (1994) Triglyceride rich lipoproteins isolated by selected affinity antiapolipoprotein B immunosorption from human atherosclerotic plaque. Atheroscler Thromb. 14:1767-74.
Raussens et al. (2002) NMR Structure and Dynamic of a Receptor-active Apolipoprotein E Peptide. J Biol Chem. 277: 29172-80.
RCE/Response to Final Office Action filed Aug. 15, 2005 for U.S. Appl. No. 10/273,386.
RCE/Response to Final Office Action filed Jul. 13, 2009 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
RCE/Response to Final Office Action filed Jul. 13, 2009 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
RCE/Response to Final Office Action filed Nov. 15, 2004 for U.S. Appl. No. 09/896,841 (17 pages).
RCE/Response to Final Office Action filed Oct. 18, 2006 for U.S. Appl. No. 10/423,830.
RCE/Response to Final Office Action filed Oct. 7, 2005 for U.S. Appl. No. 10/187,215.
Reape and Groot (1999) Chemokines and atherosclerosis. Atherosclerosis. 147:213-25.
Recent Developments in the Synthesis of Fatty Acid Derivatives. Eds. Knothe, G. and Derksen, J.T.B., AOCS Press 1999; ISBN: 1-893997-00-6.
Reddy et al. (2001) Human paraoxonase-3 is an HDLassociated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids. Arterioscler Thromb Vasc Biol. 21:542-7.
Reddy et al. (2004) Potential role for mitogen-activated protein kinase phosphatase-1 in the development of atherosclerotic lesions in mouse models. Arterioscler Thromb Vasc Biol. 24:1676-81.
Remaley et al. (2003) Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway. J Lipid Res. 44:828-36.
Rembold, C.M. (2004) Combination Therapy of Dyslipidemia in Non-Insulin-Dependent Diabetes Mellitus and the Metabolic Syndrome. Curr Diab Rep. 4(5): 330-4.
Remington: The Science and Practice of Pharmacy, 19th ed., A.R. Gennaro, Ed., Mack Publishing Company, Easton, PA (1995).
Rencurel, F. et al. (2006) Stimulation of AMP-activated protein kinase is essential for the induction of drug metabolizing enzymes by Phenobarbital in human and mouse liver. Mol Pharmacol. 70:1925-34.
Rensen, P.C., and van Berkel, T.J. (1996) Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicronlike triglyceride-rich lipid emulsions in vitro and in vivo. J Biol Chem. 271:14791-9.
Request for Certificate of Correction filed Aug. 3, 2009 for U.S. Appl. No. 10/712,447 (4 pages).
Response After Final Office Action filed on Jul. 13, 2015 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (11 pages).
Response After Final Office Action filed on Oct. 09, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Response After Final Office Action filed on Oct. 9, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Response after Non-Final Office Action filed Mar. 12, 2008 for U.S. Appl. No. 10/712,447 (14 pages).
Response to Advisory Action and Final Office Action filed Sep. 4, 2007 for U.S. Appl. No. 10/712,447 (16 pages).
Response to Ex Parte Quayle Action filed Oct. 14, 2009 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Response to Ex Parte Quayle Action filed Oct. 14, 2009 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Response to Examination Report filed Dec. 23, 2008 for New Zealand Application No. 541504 (6 pages).
Response to Examination Report filed Jul. 16, 2008 for New Zealand Application No. 541504 (18 pages).
Response to Examination Report filed Mar. 18, 2009 for New Zealand Application No. 541504 (3 pages).
Response to Final Office Action and Request for Continued Examination filed on Sep. 19, 2017 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (13 pages).
Response to Final Office Action and Request for Continued Examination filed on Sep. 19, 2017 with U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah et al.; Applicant—UAB Research Foundation) (13 pages).
Response to Final Office Action filed Jul. 3, 2006 for U.S. Appl. No. 10/273,386.
Response to Final Office Action filed Jul. 31, 2007 for U.S. Appl. No. 10/712,447(15 pages).
Response to Final Office Action filed on May 9, 2013 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (18 pages).
Response to Final Office Action filed Sep. 28, 2010 for U.S. Appl. No. 11/405,601 (20 pages).
Response to Non-Final Office Action filed Apr. 23, 2004 for U.S. Appl. No. 09/896,841 (23 pages).
Response to Non-Final Office Action filed Dec. 21, 2004 for U.S. Appl. No. 10/273,386.
Response to Non-Final Office Action filed Feb. 28, 2005 for U.S. Appl. No. 10/187,215.
Response to Non-Final Office Action filed Jan. 20, 2006 for U.S. Appl. No. 10/273,386.
Response to Non-Final Office Action filed Jul. 12, 2004 for U.S. Appl. No. 10/187,215 (18 pages).
Response to Non-Final Office Action filed Jul. 17, 2008 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Response to Non-Final Office Action filed Jul. 17, 2008 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Response to Non-Final Office Action filed Mar. 20, 2006 for U.S. Appl. No. 10/187,215.
Response to Non-Final Office Action filed May 27, 2003 for U.S. Appl. No. 09/645,454.
Response to Non-Final Office Action filed Nov. 29, 2006 for U.S. Appl. No. 10/712,447 (21 pages).
Response to Non-Final Office Action filed Oct. 19, 2005 for U.S. Appl. No. 10/423,830.
Response to Non-Final Office Action filed on Apr. 10, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (15 pages).
Response to Non-Final Office Action filed on Apr. 10, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (15 pages).
Response to Non-Final Office Action filed on Aug. 14, 2018 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (12 pages).
Response to Non-Final Office Action filed on Jan. 12, 2015 with the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (17 pages).
Response to Non-Final Office Action filed on Jan. 15, 2015 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (13 pages).
Response to Non-Final Office Action filed on Jan. 4, 2017 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (10 pages).
Response to Non-Final Office Action filed on Mar. 25, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Appliant—UAB research Foudation) (14 pages).
Response to Non-Final Office Action filed on Mar. 25, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (14 pages).
Response to Non-Final Office Action filed on Mar. 26, 2013 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (11 pages).
Response to Non-Final Office Action filed on Mar. 26, 2013 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (11 pages).
Response to Non-Final Office Action filed on Nov. 1, 2011 with the U.S. Patent and Trademark Office for U.S. App. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Response to Non-Final Office Action filed on Nov. 1, 2011 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Response to Non-Final Office Action filed on Oct. 10, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (10 pages).
Response to Non-Final Office Action filed on Oct. 10, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (10 pages).
Response to Non-Final Office Action filed on Oct. 29, 2012 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (16 pages).
Response to Non-Final Office Action filed Sep. 3, 2008 for U.S. Appl. No. 10/712,447 (9 pages).
Response to Non-Final Rejection filed Oct. 9, 2009 for U.S. Appl. No. 11/405,601 (17 pages).
Response to Office Action filed Feb. 10, 2010 for Canadian Application No. 2,514,303 (19 pages).
Response to Office Action filed Mar. 29, 2011 for Canadian Application No. 2,514,303 (11 pages).
Response to Restriction Reqirement filed Nov. 19, 2003 for U.S. Appl. No. 10/187,215 (17 pages).
Response to Restriction Requirement filed Aug. 25, 2003 for U.S. Appl. No. 09/896,841 (16 pages).
Response to Restriction Requirement filed Dec. 12, 2002 for U.S. Appl. No. 09/645,454.
Response to Restriction Requirement filed Jul. 25, 2008 for U.S. Appl. No. 11/405,601 (8 pages).
Response to Restriction Requirement filed Mar. 1, 2005 for U.S. Appl. No. 10/423,830.
Response to Restriction Requirement filed Mar. 16, 2006 for U.S. Appl. No. 10/712,447 (10 pages).
Response to Restriction Requirement filed Mar. 17, 2009 for U.S. Appl. No. 11/405,601 (5 pages).
Response to Restriction Requirement filed May 3, 2004 for U.S. Appl. No. 10/273,386.
Response to Restriction Requirement filed Nov. 23, 2007 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Response to Restriction Requirement filed Nov. 23, 2007 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Response to Restriction Requirement filed on Apr. 25, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Response to Restriction Requirement filed on Feb. 5, 2016 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Response to Restriction Requirement filed on Jul. 23, 2013 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Response to Restriction Requirement filed on May 16, 2012 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (9 pages).
Response to Restriction Requirement filed on May 22, 2013 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, filed Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (11 pages).
Response to Restriction Requirement filed on May 22, 2013 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, which was filed on Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (11 pages).
Response to Restriction Requirement filed on Sep. 1, 2017 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant-UAB Research Foundation) (5 pages).
Response to Restriction Requirement filed on Sep. 12, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Response to Restriction Requirement filed on Sep. 12, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Response to Restriction Requirement filed on Sep. 27, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Invento—Anantharamaiah et al.; Applicant—UAB research Foundation).
Response to Restriction Requirement filed on Sep. 27, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Restriction Requirement dated Apr. 16, 2012 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applican—UAB Research Foundation) (7 pages).
Restriction Requirement dated Aug. 12, 2010 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (7 pages).
Restriction Requirement dated Aug. 21, 2007 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Restriction Requirement dated Dec. 18, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement dated Feb. 1, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Restriction Requirement dated Feb. 16, 2006 for U.S. Appl. No. 10/712,447 (9 pages).
Restriction Requirement dated Feb. 19, 2004 for U.S. Appl. No. 10/273,386.
Restriction Requirement dated Feb. 20, 2003 for U.S. Appl. No. 09/896,841 (4 pages).
Restriction Requirement dated Feb. 7, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, filed Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applican—UAB Research Foundation) (11 pages).
Restriction Requirement dated Jul. 15, 2003 for U.S. Appl. No. 10/187,215 (4 pages).
Restriction Requirement dated Jul. 9, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Restriction Requirement dated Jun. 26, 2008 for U.S. Appl. No. 11/405,601 (11 pages).
Restriction Requirement dated Mar. 6, 2017 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement dated Nov. 27, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (7 pages).
Restriction Requirement dated Nov. 9, 2004 for U.S. Appl. No. 10/423,830.
Restriction Requirement dated Oct. 14, 2005 for U.S. Appl. No. 10/712,447 (9 pages).
Restriction Requirement dated Sep. 12, 2002 for U.S. Appl. No. 09/645,454.
Restriction Requirement issued Aug. 21, 2007 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Restriction Requirement issued Feb. 16, 2006 for U.S. Appl. No. 10/712,447 (9 pages).
Restriction Requirement issued Feb. 19, 2004 for U.S. Appl. No. 10/273,386.
Restriction Requirement issued Feb. 20, 2003 for U.S. Appl. No. 09/896,841 (4 pages).
Restriction Requirement issued Jul. 15, 2003 for U.S. Appl. No. 10/187,215 (4 pages).
Restriction Requirement issued Jun. 26, 2008 for U.S. Appl. No. 11/405,601 (11 pages).
Restriction Requirement issued Nov. 9, 2004 for U.S. Appl. No. 10/423,830.
Restriction Requirement issued Oct. 14, 2005 for U.S. Appl. No. 10/712,447 (9 pages).
Restriction Requirement issued on Apr. 16, 2012 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement issued on Aug. 12, 2010 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (7 pages).
Restriction Requirement issued on Dec. 18, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement issued on Feb. 1, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Restriction Requirement issued on Feb. 7, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, which was filed on Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (11 pages).
Restriction Requirement issued on Jul. 9, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Restriction Requirement issued on Mar. 6, 2017 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement issued on Nov. 27, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (7 pages).
Restriction Requirement issued Sep. 12, 2002 for U.S. Appl. No. 09/645,454.
Ridker, P. M. (2002) On evolutionary biology, inflammation, infection, and the causes of atherosclerosis. Circulation. 105:2-4.
Roessler, J. et al. (1993) Adenoviral-mediated gene transfer to rabbit synovium in vivo. J Clin Invest. 92:1085-92.
Rogers, et al. (1998) The lipid-free structure of apolipoprotein A-I: effects of aminoterminal deletions. Biochemistry. 37:11714-25.
Roher et al. (1993) β-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: Implications for the pathology of Alzheimer disease. Proc Natl Acad Sci USA. 90:10836-40.
Rohlmann, A. et al. (1998) Inducible Inactivation of Hepatic LRP Gene by Cre-mediated Recombination Confirms Role of LRP in Clearance of Chylomicron Remnants. J Clin Invest. 101:689-95.
Romá´n et al. (2002) Subcortical ischaemic vascular dementia. Lancet Neurol. 1:426-36.
Rong et al. (2001) Elevating high-density lipoprotein cholesterol in apolipoprotein E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content. Circulation. 104:2447-52.
Roscoe, H.G. and A.W. Vogel (1968) Lipid Changes in the Eye Concomitant with the Development of Atherosclerosis in the Aorta in the Rabbit. Circ Res. 23(5): 633-43.
Rose, D.J. (1993) Characterization of antisense binding properties of peptide nucleic acids by capillary gel electrophoresis. Anal Chem. 65(24):3545-9.
Rubin et al. (1991) Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 353:265-7.
Sabbatini et al. (2001) Microanatomical changes of intracerebral arteries in spontaneously hypertensive rats: a model of cerebrovascular disease of the elderly. Mech Aging Dev. 122:1257-68.
Sabbatini et al. (2001) Microanatomical changes of intracerebral arteries in spontaneously hypertensive rats: a model of cerebrovasular disease of the elderly. Mech Aging Dev. 122:1257-68.
Saison-Behmoaras et al. (1991) Short modified antisense oligonucleotides directed against Ha-ras point mutation induce selective cleavage of the mRNA and inhibit T24 cells proliferation. EMBO J. 10:1111-8.
Sandana Mala, J.G. et al. (2001) Strain improvement of Aspergillus niger for enhanced lipase production. J Gen Appl Microbiol. 47 (4):181-6.
Sattler, W. and Stocker, R. (1993) Greater selective uptake by Hep G2 cells of highdensity lipoprotein cholesteryl ester hydroperoxides than of unoxidized cholesterylesters. Biochem J. 294:771-8.
Schmitz-Peiffer C. (2000) Signaling aspects of insulin resistance in skeletal muscle: mechanisms induced by lipid oversupply. Cell Signal. 12(9-10):583-94.
Schnölzer et al. (1992) Constructing proteins by dovetailing unprotected synthetic peptides: backbone-engineered HIV protease. Science. 256: 221.
Schönbeck, U. and Libby, P. (2004) Inflamation, Immunity, and HMG-COA Reductase Inhibitors, Statins as Anti inflammatory Agents? Circulation. 109(21 Suppl 1):II18-26.
Schonfeld et al. (1979) Lipolysis produces changes in the immunoreactivity and cell reactivity of very low density lipoproteins. J Clin Invest. 64:1288-97.
Segrest et al, (1974) A Molecular Theory of Lipid-Protein Interaction in the Plasma Lipoproteins. FEBS Left. 38: 247-253.
Segrest et al. (1990) Amphipathic Helix Motif: Classes and Properties. Proteins: Struct, Funct. Genet. 8:103-17.
Segrest et al. (1994) ApoB-100 has a pentapartite structure composed of three amphipathic alpha-helical domains alternating with two amphipathic beta-strand domains. Detection by the computer program LOCATE. Arterioscler Thromb. 14:1674-85.
Segrest et al. (1998) Apolipoprotein B-100: conservation of lipidassociating amphipathic secondary structural motifs in nine species of vertebrates. J Lipid Res. 39:85-102.
Segrest, J.P. et al., Structure of Apolipoproteins B-100 in Low Density Lipoproteins. J Lipid Res. 2001; 42(9):1346-67.
Segrest, J.P. et al., The Amphipathic Helix in the Exchangeable Apolipoproteins: A Review of Secondary Structure and Function. J Lipid Res. 1992; 33(2):141-66.
Senior (1999) New options developed for needle-free drug delivery. Lancet. 1998:354:1102.
Seth, et al. (1984) Evidence that the Penton Base of Adenovirus is Involved in Potentiation of Toxicity of Pseudomonas Exotoxin Conjugated to Epidermal Growth Factor. Mol Cell Biol. 4:1528-33.
Seth, et al. (1984) Role of a low-pH environment in adenovirus enhancement of the toxicity of a Pseudomonas exotoxin-epidermal growth factor conjugate. J Virol. 51:650-5.
Shah et al. (1998) Effects of recombinant apolipoprotein A-I(Mi.lano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation. 97(8):780-5.
Shah et al. (2001) High-dose recombinant apolipoproteins A-Imilano mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophase content in apolipoprotein Edeficient mice: potential implications ofr acute plaque stabilization. Circulation. 103:3047-50.
Shah, P.K. et al. (2005) Apolipoprotein A-I mimetic peptides: potential role in atherosclerosis management. Trends Cardiovasc Med. 15:291-6.
Sharp, R.J. et al. (2004) Structural Features of Apolipoprotein B Synthetic Peptides that Inhibit Lipoprotein(a) Assembly. J Lipid Res. 45(12):2227-34.
Shea et al. (1990) Synthesis, hybridization properties and antiviral activity of lipid-oligodeoxynucleotide conjugates. Nucl Acids Res. 18:3777-83.
Shen, B.W. et al. (1977) Structure of human serum lipoproteins inferred from compositional analysis. Proc Natl Acad Sci USA. 74:837-41.
Shih et al. (1999) Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating beta integrin. J Clin Invest. 103:613-25.
Shih et al. (2000) Combined serum paraoxonase/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem. 275:17527-35.
Shimano, H. et al., Plasma Lipoprotein Metabolism in Transgenic Mice Overexpressing Apolipoprotein E. Accelerated Clearance of Lipoproteins Containing Apolipoprotein B. J Clin Invest. 1992; 90(5):2084-91.
Shishehbor et al. (2003) Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA. 289(13):1675-80.
Silkensen et al. (1999) Identification of clusterin sequences mediating renal tubular cell interactions. J Peptide Res. 54:449-47.
Singh et al. (2000) Innate defences against viremia. Rev Med Virol. 10:395-403.
Sonntag et al. (1997) Decreases in Cerebral Microvasculature with Age are Associated with the Decline in Growth Hormone and Insulin-Like Growth Factor 1. Endocrinology. 138(8): 3515-20.
Sorescu et al. (2001) NAD(P)H oxidases and their relevance to atherosclerosis. Trends Cardiovasc Med. 11:124-31.
Spangenberg, J. and L.K. Curtiss, Influence of Macrophage-Derived Apolipoprotein E on Plasma Lipoprotein Distribution of Apolipoprotein A-I in Apoprotein E-Deficient Mice. Biochim Biophys Acta. 1997; 1349:109-21.
Sparrow, C.P. et al. (2002) A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABC A1-mRNA and stimulating cholesterol efflux. J Biol Chem. 277:10021-7.
Sparrow, C.P. et al. (2002) A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABC Al-mRNA and stimulating cholesterol efflux. J Biol Chem. 277:10021-7.
Sparrow, J.T. et al., Apolipoprotein E: Phospholipid Binding Studies with Synthetic Peptides from the Carboxyl Terminus. Biochemistry. 1992; 31(4):1065-8.
Spatola Vega Data 1(3) Peptide Backbone Modifications (1982) (general review).
Spatola, A.F., Structure-Activity Relationships of Enkephalins Containing Serially Replaced Thiomethylene Amide Bond Surrogates. Life Sci. 1986; 38(14):1243-9.
Spatola, Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins. B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983).
Spieker et al. (2002) High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation. 105:1399-402.
Sprecher et al. (1993) The Low HDL Cholesterol/High Triglyceride Trait. Arterioscler Thromb. 13: 495-504.
Springer, T.A. (1990) Adhesion receptors of the immune system. Nature. 346:425-34.
Srinivas et al. (1990) Antivrial Effects of Apolipoprotein A-I and Its Synthetic Amphipathic Peptide Analogs. Virology. 176:48-57.
Stannard et al. (2001) Inability of plasma high-density lipoproteins to inhibit cell adhesion molecule expression in human coronary artery endothelial cells. Atherosclerosis. 154:31-8.
Steinberg, D. and J.L. Witztum, Inhibition of PCSK9: A Powerful Weapon for Achieving Ideal LDL Cholesterol Levels. Proc Natl Acad Sci USA. 2009; 106(24):9546-7.
Steinberg, D. et al., Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia. Circulation. 2008; 118(6):672-7.
Steplewski et al. (1985) Isolation and characterization of anti-monosialoganglioside monoclonal antibody 19-9 class-switch variants. Proc Natl Acad Sci USA. 82: 8653.
Structure and Molecular Properties 2nd ed., T.E. Creighton, W.H. Freeman and Company, New York (1993).
Sugatani et al. (1996) High-density lipoprotein inhibits the synthesis of platelet-activating factor in human vascular endothelial cells. J Lipid Mediators Cell Signal. 13:73-88.
Sumitra et al. (2001) Experimental myocardial necrosis in rats: role of arjunolic acid on platelet aggregation, coagulation and antioxidant status. Mol Cell Biochem. 224(1-2): 135-42.
Supplemental Response to Non-Final Office Action filed on Dec. 5, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Supplemental Response to Non-Final Office Action filed on Dec. 5, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Supplementary European Search Report dated Apr. 8, 2011 by the European Patent Office for European Patent Application No. 08798802.8, which was filed on Aug. 27, 2008 and granted as 2195331 on Nov. 20, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Supplementary European Search Report dated Apr. 8, 2011 by the European Patent Office for European Patent Application No. 08829135.6, which was filed on Mar. 26, 2010 and published as 2195340 on Jun. 16, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Supplementary European Search Report dated Feb. 2, 2018 by the European Patent Office for Patent Application No. 15826625.4, which was filed on Jul. 20, 2015 and published as EP 3189069 on Jul. 12, 2017 (Inventor—Anatharamaiah et al.; Applicant—UAB Reasearch Foundation et al.) (10 pages).
Supplementary European Search Report dated Nov. 29, 2011 by the European Patent Office for patent application No. 03783409.0, which was filed on Nov. 13, 2003 and published as 1599173 on Nov. 30, 2005 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (3 pages).
Supplementary European Search Report issued on Apr. 8, 2011 by the European Patent Office for European Patent Application No. 08798802.8, which was filed on Aug. 27, 2008 and granted as 2195331 on Nov. 20, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Supplementary European Search Report issued on Apr. 8, 2011 by the European Patent Office for European Patent Application No. 08829135.6, which was filed on Mar. 26, 2010 and published as 2195340 on Jun. 16, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Supplementary European Search Report issued on Feb. 2, 2018 by the European Patent Office for Patent Application No. 15826625.4, which was filed on Jul. 20, 2015 and published as EP 3189069 on Jul. 12, 2017 (Inventor—Anatharamaiah et al.; Applicant—UAB Reasearch Foundation et al.) (10 pages).
Supplementary European Search Report mailed on Nov. 29, 2011 by the European Patent Office for patent application No. 03783409.0, which was filed on Nov. 13, 2003 and published as 1599173 on Nov. 30, 2005 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (3 pages).
Suresh, R. et al. (1992) Alterations in human gingival glycosaminoglycan pattern in inflammation and in phenytoin induced overgrowth. Mol Cell Biochem. 115(2):149-54.
Svensson, U. (1985) Role of vesicles during adenovirus 2 internalization into HeLa cells. J Virology. 55:442-9.
Swain, J. et al. (1995) Prooxidant iron and copper, with ferroxidase and xanthine oxidase activities in human atherosclerotic material. FEBS Lett. 368(3):513-5.
Swarnakar et al. (2001) The apolipoprotein E-dependent low density lipoprotein cholesteryl ester selective uptake pathway in murine adrenocortical cells involves chondroitin sulfate proteoglycans and an alpha 2-macroglobulin receptor. J Biol Chem. 276:21121-6.
Swift, L.L. et al. (2001) A recycling pathway for resecretion of internalized apolipoprotein E in liver cells. J Biol Chem. 276:22965-70.
Takahashi, S.Y. et al. (1992) Rabbit very low density lipoprotein receptor-a low density receptor like protein with distinct ligand specificity. Proc Natl Acad Sci USA. 89: 9252-6.
Tam et al. (1997) Interaction of a recombinant form of apolipoprotein[a] with human fibroblasts and with the human hepatoma cell line HepG2. J Lipid Res. 37(3): 518-33.
Tam, S.P. et al., Interaction of a Recombinant Form of Apolipoprotein[a] with Human Fibroblasts and with Human Hepatoma Cell Ilne HepG2. J Lipid Res. 1997; 37(3):518-33.
Tan et al. (1997) A Novel, highly Efficient Peptide-HLA Class TH:ca Binding Assay using unfolded heavy change molecules: Identification of HIV-1 Derived Peptides that Bind to FILA-A* 0201 and HLA-A* 0301. J Immunol Methods. 205:201-9.
Terminal Disclaimer accepted Feb. 12, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Terminal Disclaimer filed Sep. 3, 2008 for U.S. Appl. No. 10/712,447 (3 pages).
Thomas, E.C. (1999) Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Rev. 31: 42-57.
Throngate, F.E. et al. (2000) Low levels of extrahepatic nonmacrophage ApoE inhibit atherosclerosis without correcting hypercholesterolemia in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 20:1939-45.
Tian et al. (2002) Structure-affinity relationships in the gp41 ELDKWA epitope for the HIV-1 neutralizing monoclonal antibody 2F5: effects of side-chain and backbone modifications and conformational constraints. J Peptide Res. 59:264-76.
Toyoda, K. et al (1997) Effect of Aging on Regulation of Brain Stem Circulation During hypotension. J Cerebral Blood Flow Metab. 17(6): 680-5.
Tracy, M.A., Development and Scale-up of a Microsphere Protein Delivery System. Biotechnol Prog. 1998; 14(1):108-15.
Transmittal of the International Search Report and Written Opinion dated Mar. 9, 2009 by the International Searching Authority for International Patent Application No. PCT/US2008/074470, which was filed on Aug. 27, 2008 and published as WO 2009/032693 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation).
Transmittal of the International Search Report and Written Opinion mailed on Mar. 9, 2009 by the International Searching Authority for International Patent Application No. PCT/US2008/074470, which was filed on Aug. 27, 2008 and published as WO 2009/032693 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation).
Triaggiai et al. (2004) An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat Med. 10(8):871-5.
Tsai et al. (1998) D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 44: 1081-9.
Tsao et al. (2001) Hibernation-induction Peptide and Cell Death: [D-Ala2, D-Leulenkephalin Blocks Bax-related Apoptotic Processes. Eur J Pharmacol. 428:149-51.
Tsimikas et al. (2001) Measuring Circulating Oxidized Low-Density Lipoprotein to Evaluate Coronary Risk. Circulation 103:1930-2.
Tward et al. (2002) Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation. 106:484-90.
Tytler et al. (1993) Reciprocal effects of apolipoprotein and lytic peptide analogs on membranes. Cross-sectional molecular shapes of amphipathic alpha helixes control membrane stability. J Biol Chem. 268: 2212-8.
U.S. Appl. No. 15/329,735, filed Jan. 27, 2017, Anantharamaiah.
U.S. Appl. No. 62/031,585, filed Jul. 31, 2014, Anantharamaiah.
Valabhji, J. et al. (2001) High-density lipoprotein composition and paraoxonase activity in Type I diabetes. Clin Sci (Lond). 101(6):659-70.
Van Leeuwen, R. et al. (2003) Epidemiology of age-related maculopathy: a review. Eur J Epidemiol. (9):845-54.
Van Lenten et al. (1995) Anti-inflammatory HDL Becomes Pro-inflammatory during the Acute Phase Response. J Clin Invest. 96:2758-67.
Van Lenten et al. (2002) Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide. Circulation. 106:1127-32.
Van Lenten, B.J. et al. (2001) High-density lipoprotein loses its anti-inflammatory properties during acute influenza A infection, Circulation. 103:2283-8.
Van Lenton et al. (2004) D-4F an ApoA-I mimetic peptide inhibits the inflammatory response induced by influenza A infection of human type II pneumocytes. Circulation. 110:3252-8.
Van Velzen et al., Imagining of Atherosclerosis: Invasive and Noninvasive Techniques. Hellenic J Cardiol. 2009; 50:245-63.
Varga et al. (1991) Infectious entry pathway of adenovirus type 2. J Virol. 65:6061-70.
Vaughan, C.J. et al., the Evolving Role of Statins in the Management of Atherosclrosis. J Am Coll Cardiol. 2000; 35(1):1-10.
Venugopal et al. (2002) Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 106:1439-41.
Verhoeyen et al. (1988) Reshaping human antibodies: grafting an antilysozyme activity. Science. 239:1534-6.
Vinters et al. (1998) Secondary microvascular degeneration in amyloid angiopathy of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). Acta Neuropathol. 95:235-44.
Vitamins, or the Combination for the Prevention of Coronary Disease. N Engl J Med. 345(22):1583-92.
Vovenko, E. (1999) Distribution of oxygen tension on the surface of arterioles, capillaries and venules of brain cortex and in tissue in normoxia; an experimental study on rats. Eur J Physiol. 437:617-23.
Wake, A.K. et al. (2008) Apolipoprotein A-1 mimetic peptide retains function after oxidant exposure. Proc ASME 2008 Summer Bioenginerring Conference (Marco Island, Florida), Jun. 25-29, 2008, SBC2008-189660.
Walpola et al. (1995) Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress. Arterioscler Thromb Vasc Biol. 15:2-10.
Watson et al. (1995) Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized-low gensitylipoprotein. J Clin Invest. 95:774-82.
Watson et al. (1995) Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 96:2882-91.
Watts et al. (1998) Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: a hypothesis. Atherosclerosis. 141:17-30.
Weers, P.M. et al. (2001) Modulation of the lipid binding properties of the N-terminal domain of human apolipoprotein E3. Eur J Biochem. 268(13): 3728-35.
Wei et al. (1998) Antioxidants Inhibit ATP-Sensitive Potassium Channels in Cerebral Arterioles. Stroke. 29: 817-23.
White, C. R. et al. (1994) Superoxide and peroxynitrite in atherosclerosis. Proc Natl Acad Sci USA. 91:1044-8.
White, C.R. et al. (1996) Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits. Proc Natl Acad Sci USA. 93:8745-9.
Wickham et al. (1993) Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell. 73:309-19.
Wilson, C. et al., Three-Dimensional Structure of the LDL receptor-Binding Domain of Human Apolipoprotein E. Science. 1991; 252(5014):1817-22.
Witztum, J.L. et al. (1991) Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 88:1785-92.
Wolff, J.A. et al. (1990) Direct gene transfer into mouse muscle in vivo. Science. 247(4949 Pt 1): 1465-8.
Wool, G.D. et al. (2008) Apolipoprotein A-I mimetic peptide helix No. and helix linker influence potentially anti-atherogenic properties. J Lipid Res. 49(6): 1268-83.
Wool, G.D. et al. (2008) Apolipoprotein A-I mimetic peptide helix number and helix linker influence potentially anti-atherogenic properties. J Lipid Res. 49(6): 1268-83.
Wool, G.D. et al. (2009) An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide. J Lipid Res. 50(9): 1889-900.
Wu, G. et al. (1998) Effect of human apolipoprotein E isoforms on plasma lipids, lipoproteins and apolipoproteins in apolipoprotein E deficient mice. Atherosclerosis. 141:287-96.
Xia et al. (1999) High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway. A possible mechanism for protection against atherosclerosis by HDL. J Biol Chem. 274:33143-7.
Yamada, N. et al., Increased Clearance of Plasma Cholesterol After Injection of Apolipoprotein E into Wtanabe Heritable Hyperlipidemic Rabbits. Proc Natl Acad Sci USA. 1989; 86(2):665-9.
Yamamoto et al. (1995) Overexpression of Apolipoprotein E Prevents Development of Diabetic Hyperlipidemia in Transgenic Mice. Diabetes. 44(5):580-5.
Yamamoto et al. (1995) Overexpression of Apolipoprotein E Prevents Development of Diabetic Hyperlipidermia in Transgenic Mice. Diabetes. 44(5):580-5.
Yamashita et al. (2000) Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia. Atherosclerosis. 152:271-85.
Yan et al. (2004) PLTP deficiency improves the anti-inflammatory properties of HDL and reduces the ability of LDL to induce monocyte chemotactic activity. J Lipid Res. 45:1852-8.
Yancey et al. (1995) Efflux of Cellular Cholesterol and Phospholipid to Lipid-free Apolipoproteins and Class A Amphipathic Peptides. Biochemistry. 34:7955-65.
Yip, K.-P. and Marsh, D.J. (1997) An Arg-Gly-Asp peptide stimulates constriction in rat afferent arteriole. Am J Physiol. 273(5 Pt 2): F768-76.
Yla-Herttuala, S. et al. (1991) Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions. Proc Natl Acad Sci USA. 88:10143-7.
Yokoyama et al. (1980) The mechanism of activation of lecithin: cholesterol acyltransferase by apolipoprotein A-I and an amphiphilic peptide. J Biol Chem. 255:7333-9.
Yu et al. (2004) Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation. 110:66-73.
Yuan and Altman (1995) Substrate recognition by human RNase P: identification of small, model substrates for the enzyme. EMBO J. 14:159-68.
Yuan et al. (1992) Targeted cleavage of mRNA by human RNase P. Proc Natl Acad Sci USA 89:8006-10.
Yui et al. (1988) Serum prostacyclin stabilizing factor is identical to apolipoprotein A-I (Apo A-I). A novel function of Apo A-1. J Clin Invest. 82: 803-7.
Zabner et al. (1993) Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell. 75:207-16.
Zabner et al. (1994) Safety and efficacy of repetitive adenovirus-mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats. Nat Genet. 6:75-83.
Zaiou et al. (2000) Apolipoprotein E-low density lipoprotein receptor interaction. Influences of basic residue and amphipathic α-helix organization in the ligand. J Lipid Res. 41:1087-95.
Zeiher, A.M. et al. (1994) Coronary Atherosclerotic Wall Thickening and Vascular Reactivity in Humans: Elevated High-Density Lipoprotein Levels Ameliorate Abnormal Vasoconstriction in Early Atherosclerosis. Circulation. 89(6):2525-32.
Zhang et al, "Converting Peptides into Drug Leads by Lipidation," Current Medicinal Chemistry 19:1602-1618 (2012) . *
Zhang, C. et al. (2001) L-arginine chlorination products inhibit endothelial nitric oxide production. J Biol Chem. 276: 27159-65.
Zhang, R. et al (2002) Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem. 277:46116-22.
Zhang, S.H. et al., Spontaneous Hypercholesterolemia and Arterial Lesions in Mice Lacking Apolipoprotein E. Science. 1992; 258(5081):468-71.
Zhang, W.-J. et al. (2002) Lack of inhibitory effect of HDL on TNF α-induced adhesion molecule expression in human aortic endothelial cells. Atherosclerosis. 165:241-9.
Zhang, Z. et al. (2007) D-4F, An Apolipoprotein A-I Mimetic Peptide, Prevents Endothelial Dysfunction Induced by Myeloperoxidase-Derived Hypochlorous Acid. FASEB J. 21:706-11 (Meeting Abstract).
Zhao et al. (2002) Selective interleukin-12 synthesis defect in 12/15- lipoxygenase deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia. J Biol Chem. 277: 35350-6.
Zhu, B. et al. (2000) Apolipoprotein E inhibits neointimal hyperplasia after arterial injury in mice. Am J Pathol. 157:1839-48.
Zhu, Y., and Hui, D.Y. (2003) Apolipoprotein E binding to low density lipoprotein receptor related protein-1 inhibits cell migration via activation of cAMP dependent protein kinase A. J. Biol. Chem. 278:36257-63.
Zilversmit, D.E. (1979) Atherogenesis: a postprandial phenomenon. Circulation. 60:473-85.
Zuker, M. (1989) On finding all suboptimal foldings of an RNA molecule. Science. 244:48-52.
Abrahmsen, L. et al. (1991) Engineering Subtilisin and its Substrates for Efficient Ligation of Peptide Bonds in Aqueous Solution. Biochemistry. 30(17): 4151-9.
Acsadi, G. et al. (1991) Human Dystrophin Expression in MDX mice after Intramuscular Injection of DNA Constructs. Nature. 352(6338): 815-8.
Adachi, T. et al. (2003) Binding oh Human Xanthine Oxidase to Sulphated Glycosaminoglycans on the Endothelial-Cell Surface. Biochemistry. 289(2): 523-7.
Advisory Action dated Aug. 13, 2007 for U.S. Appl. No. 10/712,447 (3 pages).
Advisory Action issued Aug. 13, 2007 for U.S. Appl. No. 10/712,447 (3 pages).
Aikawa, M. et al. (2002) Lipid Loweing Reduces Oxidative Stress and Endothelial Cal Activation in Rabbit Atheroma. Circulation. 106(11): 1390-6.
Ajees, A.A. et al. (2006) Crystal Structure of Human Apolipoprotein A-1: Insights into its Protective Effect Against Cardiovascular Diseases. Proc Natl Acad Sci USA. 103(7): 2126-31.
Ali, K. et al. (2005) Apoliopoprotein E Suppresses the Type 1 Inflammatory Response in Vivo. Circ Res. 97(9): 922-7.
Almquist et al., Synthesis and Biological Activity of a Ketomethylene Analogue of a Tripeptide Inhibitor of Angiotensin Converting Enzyme. J Med Chem. 1980; 23(12):1392-8.
Anantharamaiah, G.M. et al. (1985) Studies of Synthetic Peptide Analogs of the Amphipathic Helix: Structure of Complexes with Dimyristoyl Phosphatidylcholine. J Biol Chem. 260(18): 10248-55.
Anantharamaiah, G.M. et al. (1988) Effect of Oxidation on the Properties of Apolipoproteins A-I and A-II. J Lipid Res. 29(3): 309-18.
Anantharamaiah, G.M. et al. (1990) Use of Synthetic Peptide Analogues to Localize Lecithin: Cholesterol Acyltransferase Activating Domain in Apolipoprotein A-I. Ateriosclerosis. 10(1): 95-105.
Anantharamaiah, G.M. et al. (2001) Toward the Design of Peptide Mimics of Antiatherogenic Apolipoproteins A-I and E. Curr Sci. 81(1): 53-65.
Anantharamaiah, G.M. et al. (2006) Synthetic Peptides: Managing Lipid Disorders. Curr Opin Lipidol. 17(3): 233-7.
Anantharamaiah, G.M. et al. (2007) Structural Requirements for Antioxidative and Anti-Inflammatory Properties of Apolipoprotein A-I Mimetic Peptides. J Lipid Res. 48(9): 1915-23.
Anantharamaiah, G.M., Synthetic Peptide Analogs of Apolipoproteins. Meth Enzymol. 1986; 128:627-47.
Aoyagi, H. et al. (1988) Sytheses of Antibacterial Peptides, Gramicidin S Analogs and Designed Amphiphilic Oligopeptides. Tetrahedron. 44(3):877-86.
Applicant-Initiated Interview Summary dated Jun. 26, 2018 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (3 pages).
Applicant-Initiated Interview Summary issued on Jun. 26, 2018 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (3 pages).
Aravinda, S. et al. (2003) Aromatic-Aromatic Interactions in Crystal Structures of Helical Peptide Scaffolds Containing Projecting Phenylalinine Residues. J Am Chem Soc. 125(18): 5308-15.
Arisaph Pharmaceuticals Reports on Promising Results Presented at American Heart Association: Novel Apo A-1-Mimetic Peptide Significantly Inhibits Atherosclerosis in Preclinical Animal Study, BioSpace News, (Nov. 14, 2005) (2 pages). http://www.biospace.com/News/arisaph-pharmaceuticals-reports-on-promising/2610.
Arisaph Pharmaceuticals Reports on Promising Results Presented at American Heart Association: Novel Apo A-I-Mimetic Peptide Significantly Inhibits Atherosclerosis in Preclinical Animal Study, BioSpace News, (Nov. 14, 2005) (2 pages). http://www.biospace.com/News/arisaph-pharmaceuticals-reports-on-promising/2610.
Armitage, B. et al., Peptide Nucleic Acid-DNA Duplexes: Long Range Hole Migration from an Internally Linked Anthraquinone, Proc Natl Acad Sci USA, 94(23): 12320-5 (1997).
Ashby, D. et al., Lack of Effect of Serum Amyloid A (SAA) on the Ability of High-Density Lipoproteins to Inhibit Endothelial Cell Adhesion Molecule Expression, Atherosclerosis, 154(1): 113-21 (2001).
Ashby, D.T. et al., Factors influencing the Ability of HDL to Inhibit Expression of Vascular Cell Adhesion Molecule-1 in Endothelial Cells, Arterioscler Thromb Vasc Biol, 18(9): 1450-5 (1998).
Badimon, J.J. et al., Regression of Atherosclerosis Lesions by High Density Lipoprotein Plasma Fraction in the Cholesterol-Fed Rabbit, J Clin Invest, 85(4): 1234-41 (1990).
Baggiolini, M and I. Clark-Lewis, Interlukin-8, a Chemotactic and Inflammatory Cytokine, FEBS Lett, 307: 97-101 (1992).
Bailey, R.W. et al., Clusterin, a Binding Protein with a Molten Globule-Like Region, Biochemistry, 40(39): 11828-40 (2001).
Baker, P.W. et al., Ability of Reconstituted High Density Lipoproteins to Inhibit Cytokine-Induced Expression of Vascular Cell Adhesion Molecule-1 in Human Umbilical Vein Endothelial Cells, J Lipid Res, 40(2): 345-53 (1999).
Baker, P.W. et al., Phospholipid Composition of Reconstituted High Density Lipoproteins Influences Their Ability to Inhibit Endothelial Cell Adhesion Molecule Expression, J Lipid res, 41(8):1261-7 (2000).
Barengolts et al., Osteoporosis and Coronary Atherosclerosis in Asymptomatic Postmenopausal Woman, Calcif Tissue Int, 62(3):209-13 (1998).
Barter, P.J. and K.A. Rye, High Density Lipoproteins and Coronary Heart Disease, Atherosclerosis, 121(1): 1-12 (1996).
Baumbach et al., Cerebral Arteriolar Structure in Mice Overexpressing Human Renin and Angiotensinogen, Hypertension, 41(1): 50-5 (2003).
Baumbach et al., Structure of Cerebral Arterioles in Cystathionine β-Synthase-Deficient Deficient Mice, Circ res, 91(10): 931-7 (2002).
Baumbach et al., Structure of Cerebral Arterioles in Cystathionine β-Synthase-Deficient Mice, Circ res, 91(10): 931-7 (2002).
Beatty S, Koh H, Phil M, Henson D, Boulton M. (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 45(2):115-134.
Bechinger B. (2000) Understanding peptide interactions with the lipid bilayer: a guide to membrane protein engineering. Curr Opin Chem Biol. 4(6):639-644.
Beisiegel, U. et al. The LDL-receptor-related protein, LRP, is an apolipoprotein E-binding protein. Nature 341: 162-164 (1989).
Bergt, C. et al., (2004) The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport. Natl Acad Sci USA. 101:13032-7.
Berkner et al. (1987) Abundant Expression of Polyomavirus Middle T Antigen and Dihydrofolate Reductase in an Adenovirus Recombinant. J. Virology 61:1213-1220.
Besiegel, U. et al. (1991) Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein Proc. Natl. Acad. Sci. U.S.A. 88:8342-8346.
Betteridge, D.J., Long-term risk reduction: Who needs treatment?, Diabetes Research and Clinical Practice. (2005) 68S2:S15-2.
Bisoendial et al. (2003) Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low High-Density Lipoprotein Circulation 107: 2944-2948.
Blackburn WD Jr, et al. (1991) Apolipoprotein A-I decreases neutrophil degranulation and superoxide production. J Lipid Res. 32(12): 1911-1918.
Blankenberg et al. (2001) Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 2001; 104:1336-1342.
Boerner et al. (1991) Production of Antigen-Specific Human Monoclonal Antibodies from in Vitro-Primed Human Splenocytes. J. Immunol., 147(1):86-95.
Boffa et al., Isolation of active genes containing CAG repeats by DNA strand invasion by a peptide nucleic acid. Proc Natl Acad Sci USA. Mar. 14, 1995; 92(6): 1901-5.
Boffelli et al. (1997) Reconstitution and Further Characterization of the Cholesterol Transport Activity of the Small-Intestinal Brush Border Membrane Biochemistry 36:10784-10792.
Boffelli et al., (1997) The uptake of cholesterol at the small-intestinal brush border membrane is inhibited by apolipoproteins. FEBS Letters, 411: 7-11.
Borhani et al. (1999) Crystal structure of truncated human apolipoprotein A-1 suggests a lipid bound conformation. Proc. Natl. Acad. Sci. USA. 94:12291-12296.
Bourdillon et al. (2000) ICAM 1 deficiency reduces atherosclerotic lesions in double-knockout mice (ApoE(-/ ) IICAM-1(-/-)) fed a fat or a chow diet. Arterioscler Thromb Vasc Biol 2000;20:2630-2635.
Bowry et al. (1992) High density lipoprotein is the major carrier of lipid hydroperoxides in human blood plasma from fasting donors. Proc Natl Acad Sci USA. 1992;89:10316-10320.
Braddock. D. T., et al., (1996) Conformationally Specific Enhancement of Receptor-ediated LDL Binding and Internalization by Peptide Models of a Conserved Anionic N-Termina Domain of Human Apolipoprotein E. Biochemistry 35, 13975-13984.
Bradley et al. (1982) Apolipoprotein E degradation in human very low density lipoproteins by protease(s): chemical and biological consequences. Biochim. Biophys. Res. Commun. 109:1360-1367.
Bradley, W.A. and S.H. Gianturco, ApoE is Necessary and Sufficient for the Bidning of Large Triglyceride-Rice Lioproteins to the LDL Receptor; ApoB is Unnecessary. J Lipid Res. 1986; 27(1):40-8.
Brigham et al. (1989) Expression of a prokaryotic gene in cultured lung endothelial cells after lipofection with a plasmid vector. Am. J. Resp. Cell. Mol. Biol. 1: 95-100.
Brousseau, M.E. (2005) Emerging role of high-density lipoprotein in the prevention of cardiovascular disease. Drug Discovery Today. 10:1095-1099.
Brousseau, M.E., and Hoeg, J.M. (1999) Transgenic rabbits as models for atherosclerosis research. J. lipid Res. 40:365-375.
Brown M.L., et al. (2000) A Macrophage Receptor for Apolipoprotein B48: Clining, Expression, and Atherosclerosis. Proc. Natl. Acad. Sci. USA 97:7488-7493.
Brown, B.G. et al. (2001) Simvastatin and Niacin, Antioxidant Vitamins, or the Combination for the Prevention of Coronary Disease. N Engl J Med. 345(22):1583-92.
Brown, D.T. and Burlingham, B.T., (1973) Penetration of Host Cell Membranes by Adenovirus 2 J. Virology 12:386-396.
Burger et al. (2002) High-density lipoprotein-associated apolipoprotein A-I: the missing link between infection and chronic inflammation?Autoimmunity Reviews 2002;1:111-117.
Burnett, J.R. and Vasikaran, S.D. (2002) Cardiovascular disease and osteoporosis: is there a link between lipids and bone? Ann Clin Biochem. 39(Pt 3): 203-210.
Calabresi L, et al. (2002) Elevated cellular adhesion molecules in subjects with low ML-cholesterol. Arterioscler Thromb Vasc Biol.;22:656-661.
Calabresi L, Franceschini G, Sirtoh CR, De Palma A, Saresella M, Ferrante P, Taramelli D. Inhibition of VCAM-1 expression in endothelial cells by reconstituted high density lipoproteins. Biochem Biophys Res Commun. (1997) 238:61-65.
Calabresi, L., et al., (2003) Entothelial Protection by High-Denisty Lipoproteins. Athero. Thromb. Vasc. Biol. 23:1724-1731.
Campbell, E.J. Human leukocyte elastase, cathepesin G and lactoferrin: family of neutrophil granule glycoproteins that bind to an alveolar macrophage receptor. Proc Natl Acad Sci USA (1982) 79:6941-6945.
Cardillo, C. et al., (1997) Xanthine Oxidase Inhibition With Oxypurinol Improves Endothelial Vasodilator Function in Hypercholesterolemic but Not in Hypertensive Patients. Hypertension 30:57-63.
Carlos TM, et al. (1990) Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells. Blood;76:965-970.
Carr, A.C. et al. (2000) Oxidation of LDL by myeloperoxidase and reactive nitrogen species oxidation of LDL by myeloperoxidase and reactive nitrogen species. Arterioscler Thromb Vasc Biol; 20:1716-1723.
Carrara et al., Two helices plus a linker: A small model substrate for eukaryotic RNase P Proc. Natl. Acad. Sci. (USA) 92:2627-2631 (1995).
Casserly, I. and Topol, E. (2004) Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins. Lancet. 363:1139-46.
Castelli, W.P. et al., Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham study. JAMA. 1986. 256:2835-8. Abstract.
Catapano, A.L. et al. (1979) Suppression of 3-hydroxy-3-methylglutaryl-CoA reductase by low density lipoproteins produced in vitro by lipoprotein lipase action on nonsuppressive very low density lipo-proteins. J Biol Chem. 254:1007-9.
Certificate of Correction dated Sep. 8, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Certificate of Correction issued Sep. 8, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Certificate of Grant dated Aug. 3, 2017 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Certificate of Grant dated Dec. 11, 2014 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (97 pages).
Certificate of Grant issued on Aug. 3, 2017 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Certificate of Grant issued on Dec. 11, 2014 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (97 pages).
Charles-Schoeman, C. et al. (2008) Treatment with an apolipoprotein A-1 mimetic peptide in combination with pravastatin inhibits collagen-induced arthritis. Clin Immunol. 127(2): 234-44.
Chiesa, G. et al. (2002) Recombinant apolipoprotein A-I(Milano) infusion into rabbit carotid artery rapidly removes lipid from fatty streaks. Circ Res. 90:974-80.
Chillon, J. and Baumbach, G.L. (1999) Effects of an Angiotensin-Converting Enzyme Inhibitor and a b-Blocker on Cerebral Arterioles in Rats. Hypertension. 33: 856-61.
Chorev, M. and Goodman, M. (1995) Recent developments in retro peptides and proteins-an ongoing topochemical exploration. Trends Biotechnol. 13(10): 438-45.
Christison J, (1996) Rapid reduction and removal of HDL- but not LDL-associated cholesteryl ester hydroperoxides by rat liver in situ. Biochem J. 314:739-42.
Chung et al., (1985) Studies of Synthetic Peptide Analogs of the Amphipathic Helix. J Biol Chem. 60(18): 10256-62.
Chung, B.H. et al. (1994) Liposome-like Particles Isolated From Human Atherosclerotic Plaques are Structurally and Compositionally Similar to Surface Remnants of Triglyceride-Rich Lipoproteins. Arterioscler Thromb. 14:622-35.
Chung, B.H., et al. (1996) Probing structure and function of VLDL by synthetic amphipathic helical peptides. J Lipid Res. 37:1099-112.
Clark-Lewis et al. (1991) Chemical Synthesis, Purification, and Characterization of Two Inflammatory Proteins, Neutrophil Activating Peptide 1 (Interleukin-8) and Neutrophil Activating Peptide 2. Biochemistry. 30: 3128-35.
Clark-Lewis I, et al. (1994) Structural requirements for interleukin-8 function identified by design of analogs and CXC chemokine hybrids. J Biol Chem. 269(23): 16075-81.
Clay, M.A. et al. (1995) Localization of a domain in apolipoprotein E with both cytostatic and cytotoxic activity. Biochemistry. 34:11142-51.
Clay, M.A. et al. (2001) Time sequence of the inhibition of endothelial adhesion molecule expression by reconstituted high density liproteins, Atherosclerosis 157: 23-9.
Clee, S.M. et al. (2000) Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 hetrozygotes. J Clin Invest. 106:1263-70.
Clubb, F.J., et al. (2001) Development of atherosclerotic plaque with endothelial disruption in Watanabe heritable hyperlipidemic rabbit aortas. Cardiovasc. Pathol. 9:1-11.
Cockerill, G.W. et al. (1995) High-density lipoproteins inhibit crone-induced expression of endothelial cell adhesion molecules. Arterioscler Thromb Vasc Biol. 15:1987-94 (22 pages).
Cockerill, G.W. et al. (1999) High-density lipoproteins differentially modulate cytokine induced expression of E-selectin and cyclooxygenase-2. Arterioscler Thromb Vasc Biol. 19:910-7.
Cockerill, G.W. et al. (2001) Elevation of plasma high-density lipoprotein concentration reduces interleukin-I induced expression of E-selectin in an in vivo model of acute inflammation. Rculation. 103:108-12.
Collard, M.W. and Griswold, M.D. (1987) Biosynthesis and molecular cloning of sulfated glycoprotein 2 secreted by rat Sertoli cells. Biochemistry. 26(12):3297-303.
Colles, S.M. et al. (2001) Oxidized LDL-induced injury and apoptosis in atherosclerosis. Potential roles for oxysterols. Trends Cardiovasc Med. 11:131-8.
Corey, D.R. (1997) Peptide nucleic acids: expanding the scope of nucleic acid recognition. Trends Biotechnol. 15(6):224-9.
Coyne, E.F. et al. (2002) Methods for isolation and characterization of intracerebral arterioles in the C57/13L6 wild-type mouse. J Neurosci Meth. 120:145-53.
Cubeddu, L.X. et al., Statin Withdrawal: Clinical Implications and Molecular Mechanisms. Pharmacotherapy. 2006; 26(9):1288-96.
Cuchel, M. et al., Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open label, phase 3 study. Lancet. 2013; 381(9860):40-6.
Curcio CA, et al. (2005) Esterified and unesterified cholesterol in drusen and basal deposits of eyes with age-related maculopathy. Exp Eye Res. 81(6): 731-41.
Curcio, C.A. et al. (2001) Accumulation of cholesterol with age in human Bruch's membrane. Invest Ophthalmol Vis Sci. 42(1):265-74.
Cybulsky MI, et al. (2001) a major role for VCAM-1, but not ICAM-I, in early atherosclerosis. J Clin Invest.107:1255-62.
Cyrus, et al., (2001) Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein E-deficient mice. Circulation. 103:2277-82.
Dai et al. (2004) Implantation of Immature Neonatal Cardiac Cells Into the Wall of the Aorta in Rats: A Novel Model for Studying Morphological and Functional Development of Heart Cells in an Extracardiac Environment. Circulation. 110(3):324-9.
Dai et al. (2005) Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short- and long-term effects. Circulation 112(2):214-23.
Dansky HM, et al. (1999) Apo A-I inhibits foam cell formation in Apo E-deficient mice after monocyte adherence to endothelium. J Clin Invest. 104:31-9.
Dansky HM, et al. (2001) Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler Thromb Vasc Biol. 21:1662-7.
Dashti et al. (2004) Model class A and class L peptides increase the production of apoA-I-containing lipoproteins in HepG2 cells. J Lipid Res. 45:1919-28.
Datta et al. (2000) The Receptor Binding Domain of Apolipoprotein E, Linked to a Model Class A Amphipathic Helix, Enhances Internalization and Degradation of LDL by Fibroblasts. Biochemistry. 30:213-20.
Datta et al. (2001) Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotcin metabolism in vitro and in vivo. J Lipid Res. 42:959-66.
Datta et al. (2001) Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo. J Lipid Res. 42:959-66.
Datta et al. (2001) Effects of Increasing Hydrophobicity on the Physical-Chemical and Biological Properties of a Class A Amphipathic Helical Peptide. J Lipid Res. 42(7):1096-104.
Datta, G. et al. (2004) Aromatic Residue Position on the Nonpolar Face of Class A Amphipathic Helical Peptides Determines Biological Activity. J Biol Chem. 279:26509-17.
Datta, G. et al. (2009) Anti-inflammatory and recycling properties of an apolipoprotein mimetic peptide, Ac-hE18A-NH(2). Atherosclerosis. 2008(1): 134 (24 pages).
Davenport, P. and Tipping, P.G. (2003) The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol 163:1117-25.
Davidson, D. et al. (1987) Overproduction of Polyomavirus Middle T Antigen in Mammalian Cells through the Use of an Adenovirus Vector. J Virology. 61:1226-39.
Davidson, et al. (1994) The Influence of Apolipoprotein Structure on the Efflux of Celluar Free Cholesterol to High Density Lipoprotein. J Biol Chem. 269(37):22975-82.
Dawson, P.E. et al. (1994) Synthesis of Proteins by Native Chemical Ligations. Science. 266:776-9.
De Caterina, R. et al. (1998) Structural requirements for inhibition of cytokine-induced endothelial activation by unsaturated fatty acids. J Lipid Res. 39:1062-70.
Diederich et al. (2001) Apolipoprotein Al and HDL3 Inhibit Spreading of Primary Human Monocytes through a Mechanism that Involves Cholesterol Depletion and Regulation of CD42. Atherosclerosis. 159:313-24.
Dimayuga, P. et al. (1999) Reconstituted HDL containing human apolipoprotein A-1 reduces VCAM-1 expression and neointima formation following periadventitial cuffinduced carotid injury in apoE null mice. Biochem Biophys Res Commun. 264:465-8.
Dithmar, S. et al. (2000) Ultrastructural changes in Bruch's membrane of apolipoprotein E-deficient mice. Invest Ophthalmol Vis Sci. 41(8): 2035-42.
Domanski, M.J., Primary Prevention of Coronary Artery Disease. N Engl J Med. 2007; 357(15): 1543-5.
Dooley, C.T. et al. (1994) An All D-Amino Acid Opioid Peptide with Central Analgesic Activity from a Combinatorial Library. Science. 266:2019-22.
Dunlop, D.S. and Neidle, A. (1997) The Origin and Turnover of D-Serine in Brain. Biochem Biophys Res Commun. 235:26-30.
Duong, P. T. et al. (2006). Characterization of nascent HDL particles and macroparticles formed by ABC A1-mediated cholesterol efflux of cellular lipids to apo A-I. J Lipid Res. 47:832-43.
Dyer, C. A. et al. (1991) Only Multimers of a Synthetic Peptide of Human Apolipoprotein E are Biologically Active. J Biol Chem. 266(23):15009-15.
Dyer, C. A. et al., (1995) Structural features of synthetic peptides of apolipoprotein E that bind the LDL receptor. J Lipid Res. 36:80-8.
Dyer, C.A. and L.K. Curtiss, A Synthetic Peptide Mimic of Plasma Apolipoprotein E that Binds the LDL Receptor. J Biol Chem. 1991; 266(34):22803-6.
Dyer, C.A. et al., Only Multimers of a Synthetic Peptide of Human Apolipoprotein E are Biologically Active. J Biol Chem. 1991; 266(23):15009-15.
Ehara et al. (2001) Elevated Levels of Oxidized Low Density Lipoprotein Show a Positive Relationship With the Severity of Acute Coronary Syndromes. Circulation. 103:1955-60.
Eisenberg et al. (1992) Lipoprotein lipase enhances binding of lipoproteins to heparan sulfate on cell surfaces and extracellular matrix. J Clin Invest. 90:2013-21.
Epand et al. (1987) Studies Synthetic Peptide Analog of the Amphipathic Helix J. Biol. Chem. 262(19): 9389-96.
Epand et al. (2004) An Apolipoprotein AI Mimetic Peptide: Membrane Interactions and the Role of Cholesterol. Biochemistry. 43:5073-83.
Epand et al. (2004) Two Homologous Apolipoprotein AI Mimetic Peptides: Relationship Between Membrane Interactions and Biological Activity. J Biol Chem. 279:51404-15.
Epand, R.M. et al. (1994) HDL and apolipoprotein A-I protect erythrocytes against the generation of procoagulant activity. Arterioscler Thromb. 14(11): 1775-83.
European Search Report dated Dec. 19, 2016 by the European Patent Office for Patent Application No. 14769489.7, which was filed on Mar. 14, 2014 and published as 2996706 on Mar. 23, 2016 (Applicant—UAB Research Foundation et al.) (8 pages).
European Search Report was issued on Dec. 19, 2016 by the European Patent Office for Patent Application No. 14769489.7, which was filed on Mar. 14, 2014 and published as 2996706 on Mar. 23, 2016 (Applicant—UAB Research Foundation et al.) (8 pages).
Ex Parte Quayle Action dated Aug. 14, 2009 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Ex Parte Quayle Action issued Aug. 14, 2009 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Examination Report and Notice of Acceptance of Completed Specification dated Apr. 7, 2009 for New Zealand Application No. 541504 (2 pages).
Examination Report and Notice of Acceptance of Completed Specification issued Apr. 7, 2009 for New Zealand Application No. 541504 (2 pages).
Examination Report dated for Aug. 5, 2008 New Zealand Application No. 541504 (2 pages).
Examination Report dated Jan. 22, 2009 for New Zealand Application No. 541504 (2 pages).
Examination Report dated Sep. 21, 2017 by the Canadian Intellectual Property Office for Patent Application No. 2903869, which was filed on Mar. 14, 2013 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (6 pages).
Examination Report dated Sep. 8, 2016 by the Canadian Intellectual Property Office for Patent Application No. 2903869, which was filed on Mar. 14, 2013 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (4 pages).
Examination Report issued for Aug. 5, 2008 New Zealand Application No. 541504 (2 pages).
Examination Report issued Jan. 22, 2009 for New Zealand Application No. 541504 (2 pages).
Examination Report issued on Sep. 21, 2017 by the Canadian Intellectual Property Office for Patent Application No. 2903869, which was filed on Mar. 14, 2013 (Invento—G.M. Anantharamaiah, et al.; Applican—UAB Research Foundation) (6 pages).
Examination Report issued on Sep. 8, 2016 by the Canadian Intellectual Property Office for Patent Application No. 2903869, which was filed on Mar. 14, 2013 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (4 pages).
Examination Report No. 1 dated Dec. 3, 2012 by the Intellectual Property Office of Australia for Australian Patent Application No. 2008296487, which was filed on Mar. 11, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 1 dated Nov. 9, 2012 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 1 issued on Dec. 3, 2012 by the Intellectual Property Office of Australia for Australian Patent Application No. 2008296487, which was filed on Mar. 11, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 1 issued on Nov. 9, 2012 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 2 dated Dec. 22, 2016 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—Uab Research Foundation) (3 pages).
Examination Report No. 2 dated Jan. 6, 2014 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Examination Report No. 2 issued on Dec. 22, 2016 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Examination Report No. 2 issued on Jan. 6, 2014 by the Australian Patent Office for Australian Patent Application No. 2008295478, which was field on Aug. 27, 2008 and granted as 2008296478 on Dec. 11, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Examiner's First Report dated Apr. 30, 2008 for Australian Application No. 200390825 (2 pages).
Examiner's First Report issued Apr. 30, 2008 for Australian Application No. 200390825 (2 pages).
Extended European Search Report dated Dec. 3, 2013 by the European Patent Office for European Patent Application No. 13187186.5, which was filed on Oct. 7, 2013 and published as 2682400 on Jan. 8, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (10 pages).
Extended European Search Report dated Nov. 13, 2017 by the European Patent Office for patent application No. 17157243.1, which was filed on Feb. 21, 2017 and published as EP 3254673 on Dec. 13, 2017 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (7 pages).
Extended European Search Report issued on Dec. 3, 2013 by the European Patent Office for European Patent Application No. 13187186.5, which was filed on Oct. 7, 2013 and published as 2682400 on Jan. 8, 2014 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (10 pages).
Extended European Search Report issued on Nov. 13, 2017 by the European Patent Office for patent application No. 17157243.1, which was filed on Feb. 21, 2017 and published as EP 3254673 on Dec. 13, 2017 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (7 pages).
Farkas, M.H. et al. (2004) The recycling of apolipoprotein E and its amino-terminal 22kDA fragment: evidence for multiple redundant pathways. J Lipid Res. 45:1546-54.
Felgner et al. (1987) Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc Natl Acad Sci USA. 84:7413-7.
Field et al. (2001) Gene expression of sterol regulatory element-binding proteins in hamster small intestine. J Lipid Res. 42:1-9.
Fielding and Fielding (1995) Molecular physiology of reverse cholesterol transport. J Lipid Res. 36:211-28.
Final Office Action dated Apr. 11, 2005 for U.S. Appl. No. 10/187,215.
Final Office Action dated Apr. 21, 2017 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (19 pages).
Final Office Action dated Feb. 13, 2015 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (22 pages).
Final Office Action dated Feb. 2, 2005 for U.S. Appl. No. 10/273,386.
Final Office Action dated Jan. 10, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (21 pages).
Final Office Action dated Jan. 29, 2010 for U.S. Appl. No. 11/405,601 (10 pages).
Final Office Action dated Jun. 9, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Final Office Action dated Mar. 2, 2007 for U.S. Appl. No. 10/712,447 (7 pages).
Final Office Action dated Mar. 31, 2006 for U.S. Appl. No. 10/273,386.
Final Office Action dated May 7, 2004 for U.S. Appl. No. 09/896,841 (9 pages).
Final Office Action dated Nov. 15, 2005 for U.S. Appl. No. 10/423,830.
Final Office Action dated Sep. 11, 2008 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Final Office Action issued Apr. 11, 2005 for U.S. Appl. No. 10/187,215.
Final Office Action issued Feb. 2, 2005 for U.S. Appl. No. 10/273,386.
Final Office Action issued Jan. 29, 2010 for U.S. Appl. No. 11/405,601 (10 pages).
Final Office Action issued Mar. 2, 2007 for U.S. Appl. No. 10/712,447 (7 pages).
Final Office Action issued Mar. 31, 2006 for U.S. Appl. No. 10/273,386.
Final Office Action issued May 7, 2004 for U.S. Appl. No. 09/896,841 (9 pages).
Final Office Action issued Nov. 15, 05 for U.S. Appl. No. 10/423,830.
Final Office Action issued on Apr. 21, 2017 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (19 pages).
Final Office Action issued on Feb. 13, 2015 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (22 pages).
Final Office Action issued on Jan. 10, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (21 pages).
Final Office Action issued on Jun. 9, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Final Office Action issued Sep. 11, 2008 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
First Examination Report dated Apr. 8, 2016 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
First Examination Report dated Sep. 18, 2007 for New Zealand Application No. 541504 (2 pages).
First Examination Report issued on Apr. 8, 2016 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
First Examination Report issued Sep. 18, 2007 for New Zealand Application No. 541504 (2 pages).
First Statement of Proposed Amendments filed Sep. 18, 2008 for Australian Application No. 200390825 (13 pages).
Fleisher et al. (1982) Stimulation of arterial endothelial cell prostacyclin synthesis by high density lipoproteins. J Biol Chem. 257:6653-5.
Fogelman et al. (1980) Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci USA. 77:2214-8.
Fogelman, A.M. (2004) When good cholesterol goes bad. Nat Med. 10:902-3.
Folch, J. et al. (1957) A simple method for isolation and purification of total lipides from animal tissues. J Biol Chem. 226:497-509.
Footer et al. (1996) Biochemical evidence that a D-Loop is part of a four-strandedPNA-DNA bundle. Nickel-mediated cleavage of duplex DNA by a Gly-Gly-His-Bis-PNA. Biochemistry. 35(33): 10673-9.
Forte et al. (2002) Altered activities of anti-atherogenic enzymes LCAT, paraoxonase, and platelet-activating factor acetylhydrolase in atherosclerosis susceptible mice. J Lipid Res. 43:477-85.
Fritz, I.B. (1992) What is clusterin? Clin Exp Immunol. 88(3): 375.
Fukuda, et al. (1990) Bilayer forming ion-pair amphi-philes from single chain surfactants. J Am Chem Soc. 112:1635-7.
Further Examination dated Dec. 7, 2016 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Further Examination issued on Dec. 7, 2016 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Futterman, L.G and Lemberg, L. (2004) Statin pleiotropy: fact or fiction? Am J Crit Care. 13(3): 244-9.
Gabay C. and Kushner I. (1999) Acute-phase proteins and other systemic responses to inflammation, N Eng J Med. 340:448-54.
Gambacorti-Passerini et al. (1996) In Vitro Transcription and Translation Inhibition by Anti-PromyelocyticLeukemia (PML)/Retinoic Acid Receptor ά and Anti-PML Peptide Nucleic Acid. Blood. 88(4):1411-7.
Garber et al. (1992) Turnover of synthetic class a amphipathic peptide analogues of exchangeable apolipoproteins in rats. Correlation with physical properties. Arterioscler Thromb. 12(8): 886-94.
Garber et al. (2001) A new synthetic class A amphipathic peptide analogue protects from diet-induced atherosclerosis. J Lipid Res. 42:545-52.
Garber et al. (2001) An Arginine-rich amphipathic helical peptide mediates rapid clearance of plasma cholesterol is dyslipidemic mice. Arterioscler Thromb Vasc Biol. 21:650.
Garber, D.W. et al. (2000) A sensitive and convenient method for lipoprotein profile analysis of individual mouse plasma samples. J Lipid Res. 41:1020-6.
Garber, D.W. et al. (2003) Effect of an arginine-rich amphipathic helical peptide on plasma cholesterol in dyslipidemic mice. Atherosclerosis. 168(2):229-37.
Garber, D.W. et al., Atherosclerosis and Vascular Disease: Effects of Peptide Mimetics of Apolipoproteins. Curr Pharma Biothechnol. 2006; 7(4): 235-40.
Garner et al. (1998) Oxidation of high density lipoproteins. I. Formation of methionine sulfoxide in apolipoproteins AI and AII is an early event that accompanies lipid peroxidation and can be enhanced by alpha-tocopherol. J Biol Chem. 273:6080-7.
Garner et al. (1998) Oxidation of high density lipoproteins. I. Formation of methionine sulfoxide in apolipoproteins Al and All is an early event that accompanies lipid peroxidation and can be enhanced by alpha-tocopherol. J Biol Chem. 273 :6080-7.
Garner et al. (1998) Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residures of apolipoproteins AI and AII. J Biol Chem. 273:6088-95.
Garner et al. (1998) Oxidation of high density lipoproteins. II. Evidence for direct reduction of lipid hydroperoxides by methionine residures of apolipoproteins Al and AII. J Biol Chem. 273:6088-95.
Gaut, et al. (2002) Myeloperoxidase produces nitrating oxidants in vivo. J Clin Invest. 109:1311-9.
Geetanjali, B. et al. (2002) Changes in heat shock protein 70 localization and its content in rabbit aorta at various stages of experimental atherosclerosis. Cardiovasc Pathol. 11:97-103.
Gehrs, K.M. et al. (2006) Age-related macular degeneration—emerging pathogenetic and therapeutic concepts. Ann Med. 38(7):450-71.
George et al. (2001) 12/15-lipoxygenase gene disruption attenuates atherogenesis in LDL, receptor-deficient mice. Circulation. 104:1646-50.
Geysen, H.M. et al. (1988) Cognitive features of continuous antigenic determinants. J Mol Recognit. 1(1): 32-41.
Ghersi-Egea et al. (1996) Fate of Cerebrospinal Bluid-Borne Amyloid B-Peptide: Rapid Clearance into Blood and Appreciable Accumulation by Cerebral Arteries, J Neurochem. 67: 880-3.
Gianturco, S. et al. (1982) Receptor-mediated uptake of hypertriglyceridemic very low density lipoproteins by normal human fibroblasts. J Lipid Res. 23: 984-93.
Gianturco, S.H. et al. (1978) Control of 3-hydroxy 3-methylglutaryl CoA reductase activity in cultured human fibroblasts by VLDL of subjects with hypertriglyceredemia. J Clin Invest. 61:320-8.
Gianturco, S.H. et al. (1983) Apolipoprotein E mediates uptake of Sf 100-400 hypertriglyceridemic very low density lipoproteins by the low density lipoprotein receptor pathway in normal human fibroblasts. J Biol Chem. 258:4526-33.
Gillote et al. (1999) Apolipoprotein-mediated plasma membrane microsolubilization. Role of lipid affinity and membrane penetration in the efflux of cellular cholesterol and phospholipid. J Biol Chem. 274(4):2021-8.
Glomset, J.A. (1968) The Plasma lecithin: cholesterol acytransferase reaction. J Lipid Res. 9:155-67.
Goldstein, J.L. et al., Receptor-Mediated Endocytosis: Concepts Emerging from the LDL Receptor System. Ann Rev Cell Biol. 1985; 1:1-39.
Gomez-Foix, A.M. et al. (1992) Adenovirus-mediated Transfer of the Muscle Glycogen Phosphorylase Gene into Hepatocytes Confers Altered Regulation of Glycogen Metabolism. J Biol Chem. 267:25129-34.
Gong et al. (1994) Structural and functional properties of human and mouse apolipoprotein A-I. Biochim. Biophys. Acta. 1213:335-42; Abstract.
Goodman and Gilman, The Pharmacological Basis of Therapeutics, 11th ed., McGraw-Hill Publishing Co. (2005).
Graf, R. and Schachman, H.K. (1996) Random circular permutation of genes and expressed polypeptide chains: application of the method to the catalytic chains of aspartate transcarbamoylase. Proc Natl Acad Sci U S A. 93(21): 11591-6.
Grant of Request for Leave to Amend dated Jul. 3, 2009 for Australian Application No. 200390825 (1 page).
Grant of Request for Leave to Amend issued Jul. 3, 2009 for Australian Application No. 200390825 (1 page).
Greenaway, P.J. et al. (1982) Human cytomegalovirus DNA: BamHI, EcoRI and PstI restriction endonuclease cleavage maps. Gene. 18:355-60.
Greenaway, P.J. et al. (1982) Human cytomegalovirus DNA: BamHI, EcoRI and Pstl restriction endonuclease cleavage maps. Gene. 18:355-60.
Greene et al. Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, Inc., Somerset, NJ (1991).
Greten, F.R. et al. (2004) IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 118(3):285-96.
Griendling, K.K. et al. (2000) NAD(P)H Oxidase : Role in Cardiovascular Biology and Disease. Circulation Res. 86:494-501.
Grundy S.M., et al. (2004) Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 110:227-39.
Grundy, S.M., (1998) Hypertriglyceridemia, Atherogenic Dyslipidemia, and the Metabolic Syndrome. Am J Cardiol. 81(4A): 18B-25B.
Grundy, S.M., (1999) Hypertriglyceridemia, Insulin Resistance, and the Metabolic Syndrome. Am J Cardiol. 83(9B): 25F-9F.
Gupta et al. (2004) Calculation of Creatinine Clearance Based on Unadjusted Body Weight Leads to Errors in Renal and Heart Failure Patients. Circulation. 110(7):e70 (2 pages).
Gupta, H. et al. (2005) Apolipoprotein E mimetic Peptide dramatically lowers plasma cholesterol and restores endothelial function in watanabe heritable hyperlipidemic rabbits. Circulation. 111(23): 3112-8.
Gupta, H. et al. (2005) Inhibition of lipopolysaccharide-induced inflammatory responses by an apolipoprotein AI mimetic peptide. Circ Res. 97(3): 236-43.
Gurfinkel et al. (2002) Influenza Vaccine Pilot Study in Acute Coronary Syndromes and Planned Percutaneous Coronary Interventions. The FLU Vaccination Acute Coronary Syndromes (FLUVACS) Study. Circulation. 105:2143-7.
Guzman, R.J. et al. (1993) Efficient Gene Transfer Into Myocardium by Direct Injection of Adenovirus Vectors. Circ Res. 73:1201-7.
Haimovici, R. et al. (2001) The lipid composition of drusen, Bruch's membrane, and sclera by hot stage polarizing light microscopy. Invest Ophthalmol Vis Sci. 42(7): 1592-9.
Haj-Ahmad et al. (1986) Development of a Helper-Independent Human Adenovirus Vectorand Its Use in the Transfer of the Herpes Simplex Virus Thymidine Kinase Gene. J Virology. 57:267-74.
Halcox, J.P. et al. (2002) Prognostic Value of Coronary Vascular Endothelial Dysfunction. Circulation. 106:653-8.
Hamase et al. (2001) Determination of Free D-Proline and D-Leucine in the Brains of Mutant Mice Lacking D-Amino Acid Oxidase Activity. Anal Biochem. 298:253-8.
Handattu et al. (2006) Physical, Chemical, and Structural Studies of Apolipoprotein A-I Mimetics Correlate Well with the Efficacy for Inhibiting Atherosclerosis. Atheroscler Thromb Vasc Biol. 26(5):e64.
Handattu, S.P. et al. (2007) ApoA-I Mimetic Peptides with Differing Ability to Inhibit Atherosclerosis Also Exhibit Differences in Their Interactions with Membrane Bilayers. J Biol Chem. 282:1980-8.
Handattu, S.P. et al. (2013) Two Apolipoprotein E Mimetic Peptides with Similar Cholesterol reducing Properties Exhibit Differential Atheroprotective Effects in LDL-R Null Mice. Atherosclerosis. 227(1):58-64.
Handwerger et al. (1999) Pre-β-HDL stimulates placental lactogen release from human trophoblast cells. Am J Physiol. 276:E384-9.
Hann, M.M., On the Double Bond Isotere of the Peptide Bond: Preparation of an Enkephalin Analogue. J ChemSoc Perkin Trans 1. 1982; 307-14.
Hanvey et al. (1992) Antisense and Antigene properties of Peptide Nucleic Acids. Science. 258(5087): 1481-5.
Harats et al. (2000) Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 20:2100-5.
Hardy et al. (2001) An Automated High-Performance Liquid Chromatography Procedure for the Quantitation of L- and D-Amino Acids by Means of Stepwise Precolumn Derivatization. Anal Biochem. 291:297-9.
Harkin et al. (1997) The Effects of hyper-and hypocarbia on intraparenchymal arterioles in rat brian slices. Neuroreport. 8:1841-4.
Hashimoto (2000) Improvement of intestinal absorption of peptides: absorption of Bi-Phe monoglucosylated insulin to rat intestinal brush-border membrane vesicles. Eur J Pharm Biopharm. 50(2): 197-204.
Hasty, A.H. et al. (1999) Determination of lower threshold of apolipoprotein E resulting in lipoprotein remnant clearance. J Lipid Res. 40:1529-38.
Hauser et al. (1998) Identification of a Receptor Mediating Absorption of Dietary Cholesterol in the Intestine. Biochemistry. 37(51):17843-50.
Havel, R. J. (1985) George Lyman Duff memorial lecture. Role of the liver in atherosclerosis. Arteriosclerosis. 5: 569-80.
Hāyry et al. (1995) Stabile D peptide analog of insulin-like growth factor-1 inhibits smooth muscle cell proliferation after carotid balooning injury in the rat. FASEB J. 9(13): 1336-44.
Heeschen, C. et al., Withdrawal of Statins Increases Event Rates in Patients with Acute Coronary Syndromes. Circulation. 2002; 105(12):1446-52.
Hein, T.W. et al. (2001) Integrin-binding peptides containing RGD produce coronary arteriolar dilation via cyclooxygenase activation. Am J Physiol Heart Circ Physiol. 281(6): H2378-84.
Henriksen et al. (1981) Enhanced macrophage degradation of low density lipoprotein prevously incubated with cultured endolelial cells; recognition by receptor for acetylated low density lipoproteins. Proc Natl Acad Sci USA. 78:6499-503.
Herbert, P. et al., A Large-Scale Process to Produce Microencapsulated Proteins. Pharm Res. 1998; 15(2):357-61.
Hermanowski-Vosatka, A. et al. (2005) 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med. 202(4):517-27.
Hessler et al. (1979) LDL-induced cytotoxicity and its inhibition by 1-DL in human vascular smooth muscle and endothelial cells in culture. Atherosclerosis. 32:213-29 (Abstract).
Hoffman et al. (1997) Isoprostanes: Free Radical-Generated Prostaglandins with constrictor Effects on cerebral Arterioles. Stroke. 28: 844-9.
Holladay, M.W. and D.H. Rich, Synthesis of Hydroxyethylene and Ketomethylene Dipeptide Isoteres. Tetrahedron Lett. 1983; 24(41):4401-4.
Holvoet, P. et al. (1997) β-VLDL Hypercholesterolemia Relative to LDL Hypercholesterolemia is Associated With Higher Levels of Oxidized Lipoproteins and a More Rapid Progression of Coronary Atherosclerosis in Rabbits. Arterioscler Thromb Vasc Biol. 17:2376-82.
Hoogenboom et al. (1992) By-passing immunisation: Human antbodies from synthetic repertoires of germline VH gene segments rearranged in vitro. J Mol Biol. 227:381-8.
Hoogenboom et al. (1992) By-passing immunisation: Human antibodies from synthetic repertoires of germline VH gene segments rearranged in vitro. J Mol Biol. 227:381-8.
Houstis, N. et al. (2006) Reactive Oxygen Species Have a Causal Role in Multiple Forms of Insulin Resistance. Nature. 440: 944-8.
Hristova et al. (1999) An Amphipathic α-Helix at a Membrane Interface: A Structural Study using a Novel X-ray Diffraction Method. J Mol Biol. 290:99-117.
Hruby, V.J., Conformational Restrictions of Biologically Active Peptides via Amino Acid Side Chain Groups. Life Sci. 1982; 31(3):189-99.
Huang and Mahley, Apolipoprotein E. Structure and Function in Lipid Metabolism, Neurobiology, and Alzheimer's Diseases. Neurobiol Dis. 2014; 72PA:3-12.
Huber, M.A. et al. (2004) NF-κB is essential for epithelial-mesenchymal transition and metastasis in a model of breast cancer progression. J Clin Invest. 114(4): 569-81.
Hudson, D. et al., Methionine Enkephalin and Isoteric Analogues I. Synthesis on a Phenolic Resin Support. Int J Pept Prot Res. 1979; 14(3):177-85.
Hussain et al. (2000) High affinity binding between lipoprotein lipase and lipoproteins involves multiple ionic and hydrophobic interactions, does not require enzyme activity, and is modulated by glycosaminoglycans. J Biol Chem. 275: 29324-30.
Hwang, S.J. et al. (1997) Circulating adhesion molecules VCAM-I, ICAM-1, and E-selectin in carotid therosclerosis and incident coronary heart disease cases. The atherosclerosis risk in communities (AMC) study. Circulation. 96:4219-4225.
Hyka et al. (2001) Apolipoprotein A-I Inhibits the Production of Interleukin-10 and Tumor Necrosis Factor-a by Blocking Contact-Mediated Activation of Monocytes by T Lymphocytes. Blood. 97:2381-9.
Hyrup, B. and Nielsen, P.E. (1996) Peptide Nucleic Acids (PNA):Synthesis, Properties and Potential Applications. Bioorg Med Chem. 4(1):5-23.
Internation Preliminary Report on Patentability dated Mar. 2, 2010 by the International Searching Authority for International Patent Application No. PCT/US2008/074470, which was filed on Aug. 27, 2008 and published as WO 2009/032693 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages),
Internation Preliminary Report on Patentability issued on Mar. 2, 2010 by the International Searching Authority for International Patent Application No. PCT/US2008/074470, which was filed on Aug. 27, 2008 and published as WO 2009/032693 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
International Preliminary Examination Report dated Mar. 4, 2003 for PCT App. No. PCT/US01/26457 (5 pages).
International Preliminary Examination Report issued Mar. 4, 2003 for PCT App. No. PCT/US01/26457 (5 pages).
International Preliminary Opinion on Patentability dated Aug. 19, 2010 for PCT App. No. PCT/US2009/033415.
International Preliminary Opinion on Patentability issued Aug. 19, 2010 for PCT App. No. PCT/US2009/033415.
International Preliminary Report on Patentability dated Jan. 31, 2017 by the International Searching Authority for Patent Application No. PCT/US2015/041162, which was filed on Jul. 20, 2015 and published as WO 2016/018665 on Feb. 4, 2016 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation et al.) (6 pages).
International Preliminary Report on Patentability dated Jul. 25, 2011 for International Patent Application No. PCT/US2003/036268.
International Preliminary Report on Patentability dated Mar. 2, 2010 by the International Searching Authority for International Patent Application No. PCT/US2008/074485, which was filed on Aug. 27, 2008 and published as WO 2009/032702 on Mar. 12, 2009 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (9 pages).
International Preliminary Report on Patentability dated Sep. 24, for Patent Application No. PCT/US14/27719, which was filed on Mar. 14, 2014 and published as WO 2014/0152776 on Sep. 25, 2014 (Applicant—UAB Research Foundation//Inventor—Anantharamaiah) (8 pages).
International Preliminary Report on Patentability issued on Jan. 31, 2017 by the International Searching Authority for Patent Application No. PCT/US2015/041162, which was filed on Jul. 20, 2015 and published as WO 2016/018665 on Feb. 4, 2016 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation et al.) (6 pages).
International Preliminary Report on Patentability issued on Jul. 25, 2011 for International Patent Application No. PCT/US2003/036268.
International Preliminary Report on Patentability issued on Mar. 2, 2010 by the International Searching Authority for International Patent Application No. PCT/US2008/074485, which was filed on Aug. 27, 2008 and published as WO 2009/032702 on Mar. 12, 2009 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (9 pages).
International Preliminary Report on Patentability issued on Sep. 24, for Patent Application No. PCT/US14/27719, which was filed on Mar. 14, 2014 and published as WO 2014/0152776 on Sep. 25, 2014 (Applicant—UAB Research Foundation// Inventor—Anantharamaiah) (8 pages).
International Search Report and Written Opinion dated Dec. 15, 2015 by the International Searching Authority for Patent Application No. PCT/US2015/041162, which was filed on Jul. 20, 2015 and published as WO 2016/018665 on Feb. 4, 2016 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation et al.) (11 pages).
International Search Report and Written Opinion dated Jul. 11, 2014 for application PCT/US14/27719, which was filed on Mar. 14, 2014 and published as WO 2014/0152776 on Sep. 25, 2014 (Inventor—Anantharamaiah; Applicant—UAB Research Foundation) (27 pages).
International Search Report and Written Opinion dated Jul. 28, 2009 by the International Searching Authority for International Patent Application No. PCT/US2008/074485, which was filed on Aug. 27, 2008 and published as WO 2009/032702 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (12 pages).
International Search Report and Written Opinion dated Sep. 1, 2009 for PCT App. No. PCT/US2009/033415.
International Search Report and Written Opinion issued on Jul. 11, 2014 for application PCT/US14/27719, which was filed on Mar. 14, 2014 and published as WO 2014/0152776 on Sep. 25, 2014 (Inventor—Anantharamaiah; Applicant—UAB Research Foundation) (27 pages).
International Search Report and Written Opinion issued Sep. 1, 2009 for PCT App. No. PCT/US2009/033415.
International Search Report and Written Opinion mailed on Dec. 15, 2015 by the International Searching Authority for Patent Application No. PCT/US2015/041162, which was filed on Jul. 20, 2015 and published as WO 2016/018665 on Feb. 4, 2016 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation et al.) (11 pages).
International Search Report and Written Opinion mailed on Jul. 28, 2009 by the International Searching Authority for International Patent Application No. PCT/US2008/074485, which was filed on Aug. 27, 2008 and published as WO 2009/032702 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (12 pages).
International Search Report dated May 17, 2002 for PCT App. No. PCT/US01/26457 (3 pages).
International Search Report dated Nov. 17, 2005 for International Patent Application No. PCT/US2003/036268 (4 pages).
International Search Report issued May 17, 2002 for PCT App. No. PCT/US01/26457 (3 pages).
International Search Report issued Nov. 17, 2005 for International Patent Application No. PCT/US2003/036268 (4 pages).
Ishigami, M., et al. (2000) Apolipoprotein E inhibition of vascular smooth muscle cell proliferation but not the inhibition of migration is mediated through activation of inducible nitric oxide synthase. Arteriosc Thromb Vasc Biol. 20:1020-6.
Issue Notification dated Aug. 3, 2016 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Issue Notification dated Dec. 27, 2011 by the U.S. Patent and Trademark Office for U.S. Appl. No. 11/405,601 (1 page).
Issue Notification dated Jul. 1, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Issue Notification dated Oct. 15, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Issue Notification dated Oct. 29, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Issue Notification issued Jul. 1, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Issue Notification issued on Aug. 3, 2016 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Issue Notification issued on Dec. 27, 2011 by the U.S. Patent and Trademark Office for U.S. Appl. No. 11/405,601 (1 page).
Issue Notification issued on Oct. 15, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Issue Notification issued on Oct. 29, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Ito, M.K. et al., Management of Familial Hypercholesterolemias in Adult Patients: Recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011; 5(3 Suppl):S38-45.
Jaeger et al. (1989) Improved predictions of secondary structures for RNA. Proc Natl Acad Sci USA. 86:7706-10.
Jakobovits et al. (1993) Analysis of homozygous mutant chimeric mice: Deletion of the immunoglobulin heavy-chain joining region blocks B-cell development and antibody production. Proc Natl Acad Sci USA. 90:2551-5.
Jakobovits et al. (1993) Germ-line transmission and expression of a human-derived yeast artificial chromosome. Nature. 362:255-8.
Jamaluddin et al. (1987) Aggregatory reactions of blood platelets in ustirred dilute suspensions and their monitoring by spectrophotometry. Curr Sci. 56:254-6.
Jamieson et al. (2001) Detection of Lipoprotein(a) in Intraparenchymal Cerebral Vessels: Correlation with Vascular Pathology and Clinical History. Exp Mol Pathol. 71: 99-105.
Jennings-White, C. and R.G. Almquist, Synthesis of Ketomethylene Analogs of Dipeptides. Tetra Lett. 1982; 23(25):2533-4.
Jensen et al. (1997) Kinetics for Hybridization of Peptide Nucleic Acids (PNA) with DNA and RNA Studied with the BIAcore Technique Biochemistry. 36(16):5072-7.
Jin et al. (2003) Inhibition of endothelial lipase causes increased ML cholesterol levels in vivo. J Clin Invest. 111:357-62.
Johnson, J.H. (2006) Trends and Opportunities in the Metabolic Syndrome, Drug Dev Res. 67(7): 539-44.
Johnson, O.L. et al., A Month-Long Effect from a Single Injection of Microencapsulated Human Growth Hormone. Nature Med. 1996; 2(7):795-9.
Jones et al. (1992) Computer Programs to Identify and Classify Amphipathic a Helical Domains. J Lipid Res. 33:287-96.
Jones et al. (1992) Computer Programs to Identify and Classify Amphipathic α Helical Domains. J Lipid Res. 33:287-96.
Jong, M.C. et al. (1996) Both lipolysis and hepatic uptake of VLDL are impaired in transgenic mice coexpressing human apolipoprotein E*3Leiden human apolipoprotein C-I. Arterioscler Thromb Vasc Biol. 16:934-40.
Kabanov et al. (1990) A new class of antivirals: antisense oligonucleotides combined with a hydrophobic substituent effectively inhibit influenza virus reproduction and synthesis of virus-specific proteins in MDCK cells. FEBS Lett. 259: 327-30.
Kaler et al. (1989) Spontaneous vesicle formation in aqueous mixtures of single-tailed surfactants. Science. 245:1371-4.
Kandel ER, Schwartz JH, Jessell TM (Eds.) (1991) Principles of Neural Science, Third Edition. Elsevier: New York, pp. 188-189.
Karle et al. (1998) Crystal structure of the channel-forming polypeptide antiamoebin in a membrane-mimetic environment. Proc Natl Acad Sci USA. 95:5501-4.
Karle et al. (2003) Crystal structure of hydrophobic 19-residue peptide helix containing three centrally located D amino acids. Proc Natl Acad Sci USA. 100(24): 13946-151.
Karle et al. (2004) A combined extented and helical backbone for Boc-(Ala-Leu-Ac7C)2-OME. Peptides Res. 63:174-80.
Kaul, S. et al. (2004) Rapid Reversal of Endothelial Dysfunction in Hypercholesterolemic Apolipoprotein E-Null Mice by Recombinant Apolipoprotein A-IMilano-Phospholipid Complex. J Am Coll Cardiol. 44:1311-9.
Keech, A. et al. (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes (the FIELD study): randomised controlled trial. Lancet. 366: 1849-61.
Kidson, W. et al. (1974) Treatment of Severe Diabetes Mellitus by Insulin Infusion. Br Med J. 2(5921): 691-4.
Kirshenbaum, L.A. et al. (1993) Highly Efficient Gene Transfer into Adult Ventricular Myocytes by Recombinant Adenovirus. J Clin Invest. 92:381-7.
Kissinger, C. et al. (1982) Analysis of Sertoli cell-secreted proteins by two-dimensional gel electrophoresis. Biol Reprod. 27(1): 233-40.
Kita, T. et al. (1981) Deficiency of low density lipoprotein receptors in liver and adrenal gland of the WHHL rabbit, an animal model of familial hypercholesterolemia. Proc Natl Acad Sci USA .78: 2268-72.
Klien, R. et al. (2002) The Association of Atherosclerosis, Vascular Risk Factors, and retinopathy in Adults with Diabetes: The Atherosclerosis Risk in Communities Study. Opthalmology. 109(7): 1225-34.
Knowler, W.C. et al. (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 346(6):393-403.
Ko et al. (1993) A. Highdensity lipoprotein reduces epidermal growth factor-induced DNA synthesis in vascular smooth muscle cells. Atherosclerosis, 99: 253-9 (Abstract).
Kockx, et al. (2004) Apolipoprotein A-I-stimulated Apolipoprotein E Secretion from Human Macrophages is Independent of Cholesterol Efflux. J Biol Chem. 279:25966-70.
Koh, K.K., Effects of Statins on Vascular Wall: Vasomotor Function, Inflammation, and Plaque Stability. Cardiovasc Res. 2000; 47(4):648-57.
Kolodgie, F.D. et al. (1996) Hypercholesterolemia in the Rabbit Induced by Feeding Graded Amounts of Low-Level Cholesterol: Methodological Considerations Regarding Individual Variability in Response to Dietary Cholesterol and Development of Lesion Type. Arterioscler Thromb Vasc Biol. 16:1454-64.
Kontos, H.A. and Wei, E.P. (1998) Cerebral arteriolar dilations by KATP channel activators need L-lysine or L-arginine. Am J Physiol. 274 (3 Pt 2): H974-81.
Kowal, R.C. et al. (1989) Low density lipoprotein receptor related protein mediates uptake of cholesteryl ester derived from apolipoprotein E enriched lipoproteins. Proc Natl Acad Sci USA. 86:5810-4.
Kozbor, D. et al. (1982) Human hybridomas constructed with antigen-specific Epstein-Barr virus-transformed cell lines. Proc Natl Acad Sci USA. 79(21): 6651-5.
Kreiger (1999) Charting the Fate of the "Good Cholesterol": Identifcation and Characterization of the High-Density Lipoprotein Receptor Sr—Bi. Ann Rev Biochem. 68: 523-58.
Kullman et al. (1999) Evaluation of the Enantiomeric Composition of Amino Acids in Tobacco. Chirality. 11:669-673.
Kumar et al. (2002) A novel peptide derivative exhibits anti inflammatory and antioxidant activity in adjuvant induced arthritis in rats. Mol Cell Biochem. 229(1-2):9-17.
Kume et al. (1992) Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest. 90:1138-44.
Kwiterovich, P.O. (1998) State-of-the-art update and review: clinical trials of lipid-lowering agents. Am J Cardiol. 82: 3U-7U.
Lalazar, A. et al., Site-Specific Mutagenesis of Human Apolipoprotein E. Receptor Binding Activity of Variants with Single Amino Acd Substitutions. J Biol Chem. 1988; 263(8):3542-5.
Lawrence, M.B. and Springer, T.A. (1991) Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell. 65:859-73.
Le Gal La Salle, G. et al. (1993) An adenovirus vector for gene transfer into neurons and glia in the brain. Science. 259:988-90.
Lee, S. et al. (2001) Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science. 292:2083-6.
Legrand et al. (1992) Molecular Interactions between Human Lactotransferrin and the Phytohemagglutinin-Activated Human Lymphocyte Lactotransferrin Receptor Lie in Two Loop-Containing Regions of the N-Terminal Domain I of Human Lactotransferrin. Biochemistry. 31: 9243-51.
Letsinger et al. (1989) Cholesteryl-conjugated oligonucleotides: Synthesis, properties, and activity as inhibitors of replication of human immunodeficiency virus in cell culture. Proc Natl Acad Sci USA. 86:6553-6.
Letters of Patent dated Sep. 18, 2012 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,514,303, whichwas filed on Jul. 25, 2005 and granted on Sep. 18, 2012 (Inventor Gattadahalli et al.; Applicant—UAB research Foundation) (2 pages).
Letters of Patent issued on Sep. 18, 2012 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,514,303, whichwas filed on Jul. 25, 2005 and granted on Sep. 18, 2012 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (2 pages).
Letters Patent dated Aug. 13, 2009 for New Zealand Application No. 541504 (1 page).
Letters Patent issued Aug. 13, 2009 for New Zealand Application No. 541504 (1 page).
Levine, et al.(1993) In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci USA. 90:12040-4.
Li et al. (1993) An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arteriosc Thromb. 13:197-204.
Li, et al. (2004) Double Belt Structure of Discoidal High Density Lipoproteins: Molecular Basis for Size Heterogeneity. J Mol Biol. 343:1293-311.
Li, J.J. et al., Rebound Phenomenon of Inflammatory Response May Be a Major Mechanism Responsible for Increased Cardiovascular Events After Abrupt Cessation of Statin Therapy. Med Hypotheses. 2006; 66(6):1199-204.
Libby et al. (2002) Inflammation and atherosclerosis. Circulation. 105:1135-43.
Linsel-Nitschke, P. and Tall, A.R. (2005) HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov. 4(3): 193-205.
Mach et al. (1998) Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature. 394:200-3.
Mahley et al. (1999) Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia): questions, quandaries, and paradoxes. J Lipid Res. 40: 1933-49.
Mahley, R. W., Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology. Science. 1988; 240(4852):622-30.
Mahley, R.W. and Z.S. Ji, Remnant Lipoprotein Metabolism: Key Pathways Involving Cell-Surface Heparan Sulfate Proteoglycans and Apolipoprotein E. J Lipid Res. 1999; 40(1):1-16.
Mahley, R.W. et al. (1989) Intravenous infusion of apolipoprotein E accelerates clearance of plasma lipoproteins in rabbits. J Clin Invest. 83: 2125-30.
Manchekar, M. et al. (2004) Apolipoprotein B-Containing Lipoprotein Particle Assembly: Lipid Capacity of the Nascent Lipoprotein Particle. J Biol Chem. 279(38): 39757-66.
Manikandan et al. (2002) Antioxidant potential of a novel tetrapeptide deri-vative in isoproterenol-induced myocardial. Pharmacology. 65:105-9.
Manoharan et al. (1994) Cholic acid-oligonucleotide conjugates for antisense applications. Bioorg Med Chem Lett. 4 1053-60.
Manoharan et al. (1995) Lipidic nucleic acids. Tetrahedron Lett. 36:3651-4.
Marks et al. (1991) By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J Mol Biol. 222:581.
Massie et al. (1986) Construction of a Helper-Free Recombinant Adenovirus That Expresses Polyomavirus Large T Antigen. Mol Cell Biol. 6:2872-83.
Mato et al. (1996) Involvement of specific macrophage-lineage cells surrounding arterioles in barrier and scavenger function in brain cortex. Proc Natl Acad Sci USA. 93: 3269-74.
Mazoyer, E. et al. (1990) KRDS, a new peptide derived from human lactotransferrin, inhibits platelet aggregation and release reaction. Eur J Biochem. 194:43-9.
McGarry, J.D. (2002) Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 51(1):7-18.
Meera et al. (1999) Inhibition of neutrophil derived lysosomal enzymes and reactive oxygen species by a novel tetrapeptide. Inflamm Res. 48(9):479-84.
Mehrabian et al. (2002) Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res. 91:120-6.
Mendez et al. (1994) Synthetic Amphipathic Helical Peptides that Mimic Apolipoprotein A-I in Clearing Cellular Cholesterol. J Clin Invest. 94: 1698-705.
Merrifield et al. (1995) Retro and Retroenantio Analogs of Cecropin-Melittin Hybrids. Proc Natl Acad Sci USA. 92: 3449-53.
Mertens, A. et al. (2003) Increased Low-Density Lipoprotein Oxidation and Impaired High-Density Lipoprotein Antioxidant Defense are Associated With Increased Macrophage Homing and Atherosclerosis in Dyslipidemic Obese Mice: LCAT Gene Transfer Decreases Atherosclerosis. Circulation. 107:1640-6.
Miller, A.D. and Buttimore, C. (1986) Redesign of Retrovirus Packaging Cell Lines To Avoid Recombination Leading to Helper Virus Production. Mol Cell Biol. 6: 2895.
Miller, A.D. and Buttimore, C. (1986) Redesign of Retrovirus Packaging Cell Lines to Avoid.
Mims, M. P. et al. (1994) A Nonexchangeable Apolipoprotein E Peptide That Mediates Binding to the Low Density Lipoprotein Receptor. J. Biol. Chem. 269: 20539-647.
Miscellaneous Action dated Oct. 24, 2008 for U.S. Appl. No. 11/405,601 (2 pages).
Miscellaneous Action issued Oct. 24, 2008 for U.S. Appl. No. 11/405,601 (2 pages).
Mishra et al. (1994) Interaction of Synthetic Peptide Analogs of the Class A Amphipathic Helix with Lipids: Evidence for the Snorkel Hypothesis. J Biol Chem. 269: 7185-91.
Mishra et al. (1995) Effect of the Arrangement of Tandem Repeating Units of Class A Amphipathic α-Helixes on Lipid Interaction. J Biol Chem. 270:1602-11.
Mishra et al. (1996) Interaction of Model Class A1, Class A2, and Class Y Amphipathic Helical Peptides with Membranes. Biochemistry. 35:11210-20.
Mishra et al. (1998) Studies of Synthetic Peptides of Human Apolipoprotein A-I Containing Tandem Amphipathic α-Helixes. Biochemistry. 37: 10313-24.
Mishra et al. (2001) Solution NMR structure of a model class A (apolipoprotein) amphipathic a helical peptide. Peptides. 22:567-73.
Mishra et al. (2001) Solution NMR structure of a model class A (apolipoprotein) amphipathic α helical peptide. Peptides. 22:567-73.
Mishra et al. (2006) Association of a model class A (apolipoprotein) amphipathic a helical peptide with lipid: high resolution NMR studies of peptide lipid discoidal complexes. J Biol Chem. 281:6511-9.
Mishra et al. (2006) Association of a model class A (apolipoprotein) amphipathic α helical peptide with lipid: high resolution NMR studies of peptide lipid discoidal complexes. J Biol Chem. 281:6511-9.
Miyazaki et al. (1995) Intravenous Injection of Rabbit Apolipoprotein A-I Inhibits the Progression of Atherosclerosis in Cholesterol-Fed Rabbits. Arterioscler Thromb Vasc Biol. 15:1882-8.
Moller, D.E. and K.D. Kaufman (2005) Metabolic Syndrome: A Clinical and Molecular Perspective. Ann Rev Med. 56: 25-62.
Moore, D.J. et al. (1995) Age-related variation in the hydraulic conductivity of Bruch's membrane. Invest Ophthalmol Vis Sci. 36(7): 1290-7.
Morley, J.S., Modulation of the Action of Regulatory Peptides by Structural Modification. Trends Pharm Sci. 1(2):463-8 (1980) (general review).
Morrison et al. (1984) Chimeric human antibody molecules: Mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci USA. 81:6851-5.
Morsy et al. (1993) Efficient Adenoviral-mediated Ornithine Transcarbamylase Expression in Deficient Mouse and Human Hepatocytes. J Clin Invest. 92:1580-6.
Moullier et al. (1993) Correction of lysosomal storage in the liver and spleen of MPS VII mice by implantation of genetically madified skin fibroblast. NatGenet. 4:154-9.
Mulder et al. (2004) Low-density lipoprotein receptor-knockout mice display impaired spatial memory associated with a decreased synaptic density in the hippocampus. Neurobiol Disease. 16: 212-9.
Mulligan, R.C. (1993) The basic science of gene therapy. Science. 260:926-32.
Murugesan et al. (1994) High-density lipoprotein stimulates endothelial cell movement by a mechanism distinct from basic fibroblast growth factor. Circ Res. 74: 1149-56.
Nag et al. (1997) Cerebrovascular Changes in Chronic Hypertension Protective Effects of Enalapril in Rats. Stroke. 28: 1028-34.
Nagata et al. (1994) Distribution of free D-serine in vertebrate brains. Brain Res. 634: 291-5.
Nagata et al. (1995) Free D-serine concentration in normai and Alzheimer human brain. Brain Res Bull. 38(2): 181-3.
Nagata et al. (2002) Hemodynamic Aspects of Alzheimer's Disease. Ann N Acad Sci. 977: 391-402.
Naghavi, M. et al. (2003) Influenza infection exerts prominent inflammatory and thrombotic effects on the atherosclerotic plaques of apolipoprotein E-deficient mice. Circulation. 107(5): 762-8.
Nakamura et al. (1997) Deposition of amyloid β protein (Aβ)subtypes [Aβ40 and Aβ42(43)] in canine senile plaques and cerebral amyoloid angiopathy. Acta Neuropathol. 94: 323-8.
Nanjee et al. (1999) Acute effects of intravenous infusion of apoA-Uphosphos-phatidycholine discs on plasma lipoproteins in humans. Arterioscler Thromb Vase Biol. 19:979-89.
Nanjee et al. (2001) Intravenous apoA-1/lecithin discs increase pre-β-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans. J Lipid Res. 42:1586-93.
Navab et al. (1991) Monocyte transmigration induced by modification of low density lipoprotein in cocultures of human aortic wall cells is due to induction of monocyte chemotactic protein 1 synthesis and is abolished by high density lipoprotein. J Clin Invest. 88:2039-46.
Navab et al. (1997) Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. J Clin Invest. 99:2005-19.
Navab et al. (2000) Normal high density lipoprotein inhibits three steps in the formation of midly oxidized low density lipoprotein: step 1. J Lipid Res. 41:1481-94.
Navab et al. (2000) Normal high density lipoprotein inhibits three steps in the formation of mildly oxidized low density lipoprotein: steps 2 and 3. J Lipid Res. 41:1495-508.
Navab et al. (2001) A cell-free assay for detecting HDL that is dysfunctional in preventing the formation of or inactivating oxidized phospholipids. J Lipid Res 2001; 42:1308-17.
Navab et al. (2001) HDL and the inflammatory response induced by LDL-derived oxidized phospholipids. Arterioscler Thromb Vasc Bio.21:481-8.
Navab et al. (2003) Oral synthetic phospholipids (DMPC) raises high-density lipoprotein cholesterol levels, improves high-density lipoprotein function, and markedly reduces atherosclerosis in apolipoprotein E-null mice. Circulation. 108:1735-9.
Navab et al. (2004) Oral D-4F causes formation of pre-β high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apo;ipoprotin E-null mice. Circulation. 109:3215-20.
Navab et al. (2004) The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and L. J Lipid Res. 45: 993-1007.
Navab et al. (2005) An Apolipoprotein A-I Mimetic Works Best in the Presence of Apolipoprotein A-I. Circ. Res. 97:1085-6.
Navab et al. (2005) An oral ApoJ peptide renders HDL anti-inflammatory in Mice and Monkeys and dramatically reduces atherosclerosis in Apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol. 25:1932-7.
Navab et al. (2005) Apolipoprotein A-I Mimetic Peptides. Arterioscler Thromb Vasc Biol. 25:1325-31.
Navab et al. (2005) D-4F and Statins Synergize to Render HDL Antiinflammatory in Mice and Monkeys and Cause Lesion Regression in Old Apolipoprotein E-Null Mice. Arterioscler Thromb Vasc Biol. 25:1426-32.
Navab et al. (2005) Oral Small Peptides render HDL antiinflammatory in mice, and monkeys and reduce atherosclerosis in ApoE null mice. Circ Res. 97:524-32.
Navab et al. (2005) The double jeopardy of HDL. Ann Med 37(3):173-8.
Navab et al. (2005) The Role of High-Density Lipoprotein in Inflammation. Cardiovasc Med.15:158-61.
Navab et al., A Novel Method for Oral Delivery of Apolipoprotein Mimetic Peptides Synthesized from All L-Amino Acids. J Lipid Res. 2009; 50(8):1538-47.
Navab M, et al. (2002) Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation. 105(3): 290-2.
Navab, M. et al. (2004) Apparent Paradox of Low-Fat "Healthy" Diets Increasing Plasma Levels of Oxidized Low-Density Lipoprotein and Lipoprotein(a). Arterioscler Thromb Vasc Biol. 24:392-3.
Nguyen et al. (2006) Apolipoprotein A-I-mimetic peptides with antioxidant actions. Arch Biochem Biophys. 451:34-42.
Nicholls, S.J. et al. (2005) Formation of Dysfunctional High-Density Lipoprotein by Myeloperoxidase. Trends Cardiovasc Med. 15(6): 212-9.
Nicholls, S.J. et al. (2006) Relationship Between Atheroma Regression and Change in Lumen Size After Infusion of Apolipoprotein A-I Milano. J Am Coll Cardiol. 47(5):992-7.
Nielsen et al. (1991) Sequence-Selective Recognition of DNA by Strand Displacement with a Thymine-Substituted Polyamide. Science. 254:1497-500.
Nievelstein et al. (1991) Lipid accumulation in rabbit aortic intima two hours after bolus infusion of low density lipoprotein: A deep-etch and immuno-localization study of ultra-rapidly frozen tissue. Arterioscler Thromb. 11: 1795-805.
Nikoulin, I.R. et al. (1998) An Apolipoprotein E Synthetic Peptide Targets to Lipoproteins in Plasma and Mediates Both Cellular Lipoprotein Interactions in Vitro and Acute Clearance of Cholesterol-rich Lipoproteins in Vivo. J Clin Invest. 101(1): 223-34.
Nirmala et al. (1999) Curcumin treatment modulates collagen metabolism in isoproterenol induced myocardial necrosis in rats. Mol Cell Bioche. 197(1-2):31-7.
Nirmala, C. and Puvanakrishnan, R. (1996) Effect of curcumin on certain lysosomal hydrolases in isoproterenol-induced myocardial infarction in rats. Biochem Pharmacol. 51(1):47-51.
Nissen, S.E. et al., Effect of Recombinant ApoA-1 Milano on Coronary Atherosclerosis in Patients with Acute Coronary Syndromes: a Randomized Controlled Trial. JAMA. 2003; 290(17):2292-300.
Nofer, J.R. et al. (2004) HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest. 113:569-81.
Nomoto et al. (1998) Improvement of Intestinal Absorption of Peptide Drugs by Glycosylation: Transport of Tetrapeptide by the Sodium Ion-Dependent D-Glucose Transporter. J Phar Sci. 87(3):326-32.
Non Final Rejection dated Sep. 20, 2019 by the USPTO for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 A1 on Jan. 7, 2016 (Inventor—Gattadahalli M. Anantharamaiah, et al.) (6 pages).
Non Final Rejection was issued on Sep. 20, 2019 by the USPTO for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 A1 on Jan. 7, 2016 (Inventor—Gattadahalli M. Anantharamaiah, et al.) (6pages).
Non-Final Office Action dated Apr. 18, 2005 for U.S. Appl. No. 10/423,830.
Non-Final Office Action dated Aug. 21, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, filed Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (23 pages).
Non-Final Office Action dated Aug. 26, 2004 for U.S. Appl. No. 10/187,215 (7 pages).
Non-Final Office Action dated Jan. 13, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (15 pages).
Non-Final Office Action dated Jan. 17, 2008 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Non-Final Office Action dated Jan. 22, 2003 for U.S. Appl. No. 09/645,454.
Non-Final Office Action dated Jan. 8, 2004 for U.S. Appl. No. 10/187,215 (15 pages).
Non-Final Office Action dated Jul. 10, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (26 pages).
Non-Final Office Action dated Jul. 15, 2014 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,080, filed Apr. 21,2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (21 pages).
Non-Final Office Action dated Jul. 6, 2016 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (20 pages).
Non-Final Office Action dated Jun. 10, 2009 for U.S. Appl. No. 11/405,601 (14 pages).
Non-Final Office Action dated Jun. 13, 2008 for U.S. Appl. No. 10/712,447 (8 pages).
Non-Final Office Action dated Jun. 14, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiahet al.; Applicant—UAB research Foundation) (11 pages).
Non-Final Office Action dated Jun. 21, 2004 for U.S. App. No. 10/273,386.
Non-Final Office Action dated Jun. 29, 2012 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applican—UAB Research Foundation) (13 pages).
Non-Final Office Action dated Mar. 12, 2018 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant-UAB Research Foundation) (18 pages).
Non-Final Office Action dated May 27, 2011 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Non-Final Office Action dated May 31, 2006 for U.S. Appl. No. 10/712,447 (11 pages).
Non-Final Office Action dated Nov. 1, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Non-Final Office Action dated Nov. 19, 2007 for U.S. Appl. No. 10/712,447 (9 pages).
Non-Final Office Action dated Oct. 16, 2017 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant-UAB Research Foundation) (12 pages).
Non-Final Office Action dated Oct. 2, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Non-Final Office Action dated Oct. 21, 2003 for U.S. Appl. No. 09/896,841 (12 pages).
Non-Final Office Action dated Oct. 28, 2005 for U.S. Appl. No. 10/187,215.
Non-Final Office Action dated Sep. 7, 2005 for U.S. Appl. No. 10/273,386.
Non-Final Office Action issued Apr. 18, 2005 for U.S. Appl. No. 10/423,830.
Non-Final Office Action issued Aug. 26, 2004 for U.S. Appl. No. 10/187,215 (7 pages).
Non-Final Office Action issued Jan. 17, 2008 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Non-Final Office Action issued Jan. 22, 2003 for U.S. Appl. No. 09/645,454.
Non-Final Office Action issued Jan. 8, 2004 for U.S. Appl. No. 10/187,215 (15 pages).
Non-Final Office Action issued Jun. 10, 2009 for U.S. Appl. No. (14 pages).
Non-Final Office Action issued Jun. 13, 2008 for U.S. Appl. No. 10/712,447 (8 pages).
Non-Final Office Action issued Jun. 21, 2004 for U.S. Appl. No. 10/273,386.
Non-Final Office Action issued May 31, 2006 for U.S. Appl. No. 10/712,447 (11 pages).
Non-Final Office Action issued Nov. 19, 2007 for U.S. Appl. No. 10/712,447 (9 pages).
Non-Final Office Action issued Oct. 21, 2003 for U.S. Appl. No. 09/896,841 (12 pages).
Non-Final Office Action issued Oct. 28, 2005 for U.S. Appl. No. 10/187,215.
Non-Final Office Action issued on Aug. 21, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, which was filed on Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (23 pages).
Non-Final Office Action issued on Jan. 13, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (15 pages).
Non-Final Office Action issued on Jul. 10, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (26 pages).
Non-Final Office Action issued on Jul. 15, 2014 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (21 pages).
Non-Final Office Action issued on Jul. 6, 2016 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (20 pages).
Non-Final Office Action issued on Jun. 14, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiahet al .; Applicant—UAB research Foundation) (11 pages).
Non-Final Office Action issued on Jun. 29, 2012 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (13 pages).
Non-Final Office Action issued on Mar. 12, 2018 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, which was filed on Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (18 pages).
Non-Final Office Action issued on May 27, 2011 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728,filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Non-Final Office Action issued on Nov. 1, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Non-Final Office Action issued on Oct. 16, 2017 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (12 pages).
Non-Final Office Action issued on Oct. 2, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Non-Final Office Action issued Sep. 7, 2005 for U.S. Appl. No. 10/273,386.
Norton et al. (1995) Targeting Peptide Nucleic Acid-Protein Conjugates to Structural Features Within Duplex DNA. Bioorg Med Chem. 3(4):437-45.
Notice of Abandonment dated Mar. 12, 2014 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, filed Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (2 pages).
Notice of Abandonment dated May 13, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Notice of Abandonment dated May 21, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Notice of Abandonment issued on Mar. 12, 2014 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, which was filed on Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (2 pages).
Notice of Abandonment issued on May 13, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (1 page).
Notice of Abandonment issued on May 21, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Notice of Acceptance dated Apr. 10, 2017 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Notice of Acceptance dated Apr. 11, 2017 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Notice of Acceptance dated Oct. 14, 2008 for Australian Application No. 200390825 (3 pages).
Notice of Acceptance issued Oct. 14, 2008 for Australian Application No. 200390825 (3 pages).
Notice of Acceptance issued on Apr. 10, 2017 by the New Zealand Intellectual Property Office for Patent No. 713291, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (1 page).
Notice of Acceptance issued on Apr. 11, 2017 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Notice of Allowability issued on Jul. 22, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Notice of Allowability issued on Jul. 22, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Notice of Allowance dated Apr. 21, 2016 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Notice of Allowance dated Aug. 20, 2006 for U.S. Appl. No. 10/273,386.
Notice of Allowance dated Aug. 3, 2015 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Notice of Allowance dated Dec. 10, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Notice of Allowance dated Dec. 17, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Notice of Allowance dated Dec. 2, 2009 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Notice of Allowance dated Dec. 20, 2004 for U.S. Appl. No. 09/896,841 (5 pages).
Notice of Allowance dated Feb. 12, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (2 pages).
Notice of Allowance dated Feb. 24, 2012 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,514,303, whichwas filed on Jul. 25, 2005 and granted on Sep. 18, 2012 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (1 page).
Notice of Allowance dated Feb. 3, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (10 pages).
Notice of Allowance dated Jan. 29, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (2 pages).
Notice of Allowance dated Jun. 25, 2003 for U.S. Appl. No. 09/645,454.
Notice of Allowance dated May 1, 2006 for U.S. Appl. No. 10/187,215.
Notice of Allowance dated Nov. 21, 2006 for U.S. Appl. No. 10/423,830.
Notice of Allowance dated Sep. 9, 2011 for U.S. Appl. No. 11/405,601 (5 pages).
Notice of Allowance issued Aug. 20, 2006 for U.S. Appl. No. 10/273,386.
Notice of Allowance issued Dec. 2, 2009 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Notice of Allowance issued Dec. 20, 2004 for U.S. Appl. No. 09/896,841 (5 pages).
Notice of Allowance issued Jun. 25, 2003 for U.S. Appl. No. 09/645,454.
Notice of Allowance issued May 1, 2006 for U.S. Appl. No. 10/187,215.
Notice of Allowance issued Nov. 21, 2006 for U.S. Appl. No. 10/423,830.
Notice of Allowance issued on Apr. 21, 2016 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Notice of Allowance issued on Aug. 3, 2015 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Notice of Allowance issued on Dec. 10, 2014 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Notice of Allowance issued on Dec. 17, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Notice of Allowance issued on Feb. 12, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (2 pages).
Notice of Allowance issued on Feb. 24, 2012 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,514,303, whichwas filed on Jul. 25, 2005 and granted on Sep. 18, 2012 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (1 page).
Notice of Allowance issued on Feb. 3, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (10 pages).
Notice of Allowance issued on Jan. 29, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (2 pages).
Notice of Allowance issued on Jul. 9, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Notice of Allowance issued on Jul. 9, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and granted as 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Notice of Allowance issued Sep. 9, 2011 for U.S. Appl. No. 11/405,601 (5 pages).
Notice of Allowance with Interview Summary and Examiner's Amendment dated Feb. 24, 2009 for U.S. Appl. No. 10/712,447 (7 pages).
Notice of Allowance with Interview Summary and Examiner's Amendment issued Feb. 24, 2009 for U.S. Appl. No. 10/712,447 (7 pages).
Nuttall, M.E. an Gimble, J.M. (2000) Is there a therapeutic opportunity to either prevent or treat osteopenic disorders by inhibiting marrow adipogenesis? Bone. 27(2):177-84.
Oberhauser et al. (1992) Effective incorporation of 2′-O-methyl-oligoribonucleotides into liposomes and enhanced cell association through modification with thiocholesterol. Nucl Acids Res. 20(3):533-8.
O'Brien et al. (1996) Neovascular expression of E-selectin, inter-cellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation. 93:672-82.
Obunike, J.C. et al. (2000) The heparin-binding proteins apolipoprotein E and lipoprotein lipase enhance cellular proteoglycan production. Arterioscler Thromb Vasc Biol. 20:111-8.
O'Connell, B.J. and Genest, J., Jr. (2001) High-density lipoproteins and endothelial function. Circulation. 104:1978-83.
Office Action dated Apr. 25, 2016 by the Canadian Intellectual Poperty Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action dated Aug. 10, 2009 for Canadian Application No. 2,514,303 (3 pages).
Office Action dated Dec. 11, 2017 by the Patent Office of Japan for Patent Application No. 2016-502527, which was filed on Mar. 14, 2014 and published as 2016-515137 on May 26, 2017 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (Original-4 pages // Translation—6 pages).
Office Action dated Feb. 1, 2018 by the European Patent Office for Patent Application No. 14769489.7, which was filed on Mar. 14, 2014 and published as EP 2996706 on Mar. 22, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Office Action dated Feb. 3, 2015 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action dated Jan. 23, 2015 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,714,082, which was filed Aug. 4, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Office Action dated Jul. 23, 2013 by the Patent Office of Japan for Japanese Patent Application No. 2010-523116, which was filed on Feb. 26, 2010 and published as 2010-537638 on Dec. 9, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (13 pages).
Office Action dated Jul. 3, 2018 by the Canadian Intellectual Property Office for Patent Application No. 2,704,729, which was filed on Feb. 25, 2010 (Inventor Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Office Action dated May 6, 2017 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action dated Oct. 6, 2010 for Canadian Application No. 2,514,303 (2 pages).
Office Action dated Sep. 28, 2018 by the Intellectual Property Office of India for Patent Application No. 6250/CHENP/2015, which was filed on Oct. 9, 2015 and published on Jul. 1, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Office Action issued Aug. 10, 2009 for Canadian Application No. 2,514,303 (3 pages).
Office Action issued Oct. 6, 2010 for Canadian Application No. 2,514,303 (2 pages).
Office Action issued on Apr. 25, 2016 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action issued on Dec. 11, 2017 by the Patent Office of Japan for Patent Application No. 2016-502527, which was filed on Mar. 14, 2014 and published as 2016-515137 on May 26, 2017 (Inventor—G.M. Anantharamaiah, et al.; Applican—UAB Research Foundation) (Origina—4 pages // Translation—6 pages).
Office Action issued on Feb. 1, 2018 by the European Patent Office for Patent Application No. 14769489.7, which was filed on Mar. 14, 2014 and published as EP 2996706 on Mar. 22, 2016 (Inventor—Anantharamaiah et al.; Applican—UAB Research Foundation) (5 pages).
Office Action issued on Feb. 3, 2015 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action issued on Jan. 23, 2015 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,714,082, which was filed on Aug. 4, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Office Action issued on Jul. 3, 2018 by the Canadian Intellectual Property Office for Patent Application No. 2,704,729, which was filed on Feb. 25, 2010 (Inventor Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Office Action issued on May 6, 2017 by the Canadian Intellectual Property Office for Canadian Patent Application No. 2,704,729, which was filed on Aug. 27, 2008 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Office Action issued on Sep. 28, 2018 by the Intellectual Property Office of India for Patent Application No. 6250/CHENP/2015, which was filed on Oct. 9, 2015 and published on Jul. 1, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Office Action mailed on Jul. 23, 2013 by the Patent Office of Japan for Japanese Patent Application No. 2010-523116, which was filed on Feb. 26, 2010 and published as 2010- 537638 on Dec. 9, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Founadtion) (13 pages).
Office Action was dated Jun. 26, 2019 by the Canadian Patent Office for CA Application No. 2954475, which was filed on Jul. 20, 2015 and published as CA 2954475 Al on Feb. 4, 2016 (Applicant—UAB Research Foundation, et al.) (4 pages).
Office Action was dated Oct. 7, 2019 by the Canadian Patent Office for Canadian Application No. 2903869, filed on Mar. 14, 2014 (Applicant—U.A.B. Research Foundation, et al) (5 Pages).
Office Action was issued on Jun. 26, 2019 by the Canadian Patent Office for CA Application No. 2954475, which was filed on Jul. 20, 2015 and published as CA 2954475 A1 on Feb. 4, 2016 (Applicant—UAB Research Foundation, et al.) (4 pages).
Office Action was issued on Oct. 7, 2019 by the Canadian Patent Office for Candian Application No. 2903869, filed on Mar. 14, 2014 (Applicant—U.A.B. Research Foundation, et al.) (5 Pages).
Oguchi et al. (2000) Monoclonal antibody against vascular cell adhesion molecule-1 inhibits neointimal formation after periadventitial carotid artery injury in genetically hypercholesterolemic mice. Arterioscler Thromb Vasc Biol. 20:1729-36.
Oram and Yokoyama (1996) Apolipoprotein mediated removal of cellular cholesterol and phospholipids. J Lipid Res. 37: 2473-91.
Oram, J.F. and J.W. Heinecke, ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter that Protects Against cardiovascular Disease. Physiol Rev. 2005; 85(4): 1343-72.
Otvos, J.D. et al. (2006) Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 113(12):1556-63.
Ou et al. (2003) AP-4F, antennapedia peptide linked to an amphipathic a helical peptide, increases the efficiency of lipofectamine-mediated gene transfection in endothelial cells. Biochem Biophys Res Commun. 305:605-10.
Ou et al. (2003) L-4F, an apolipoprotein A-1 mimetic, dramatically improves vasodilation in hypercholesterolemic and sickle cell disease. Circulation. 107:2337-41.
Ou et al. (2003) L-4F, an apolipoprotein A-I mimetic, restores nitric oxide and superoxide anion balance in low-density lipoprotein-treated endothelial cells. Circulation. 107:1520-4.
Ou et al. (2005) Effects of D-4F on Vasodilation and Vessel Wall Thickness in Hyperholesterolemic LDL Receptor—Null and LDL Receptor/Apolipoprotein A-I Double-Knockout Mice on Western Diet. Circ Res. 97:1190-7.
Owens, B.J. et al. (1990) Apolipoprotein A-I and its amphipathic helix peptide analogues inhibit human immunodeficiency virus-induced syncytium formation. J Clin Invest. 86(4): 1142-50.
Paigen et al. (1990) Atherosclerosis Susceptibility Differences among Progenitors of Recombinant Inbred Strains of Mice. Arteriosclerosis. 10: 316-23.
Paka et al. (1999) Apolipoprotein E Containing High Density Lipoprotein Stimulates Endothelial Production of Heparan Sulfate Rich in Biologically Active Heparin-like Domains. J Biol Chem. 274:4816-23.
Palgunachari, M.N. et al., Only the Two End Helixes of Eight Tandem Amphipathic Helical Domains of Human Apo A-I Have Significant Lipid Affinity. Implications for HDL Assembly. Arteriosclerosis, Thromb Vasc Biol. 1996; 16(2):328-38 (27 pages).
Palinski et al. (1994) ApoE-Deficient Mice are a Model of Lipo-protein Oxidation in Atherogenesis: Demonstration of Oxidation-Specific Epitopes in Lesions and High Titers of Autoantibodies to Malondialdehyde-Lysine in Serum. Arterioscler Thromb. 14(4):605-16.
Pan, T.C. et al. (1987) Rabbit apolipoprotein A-I mRNA and gene: Evidence that rabbit apolipoprotein A-I is synthesized in the intestine but not in the liver. Eur J Biochem. 30:99-104.
Panizzutti et al. (2001) A New Strategy to Decrease N-methyl-D-aspartate (NMDA) Receptor Coactivation: Inhibition of D-serine Synthesis by Converting Serine Racemase into an Eliminase. Proc Natl Acad Sci USA. 98:5294-9.
Papo et al. (2002) The consequence of sequence alteration of an amphipathic α-helical antimicrobial peptide and its diastereomers. J Biol Chem. 277(37):33913-21.
Pappenheimer et al. (1994) Intestinal Absorption and Excretion of Octapeptides Composed of D Amino Acids. Proc Nail Acad Sci USA. 91:1942-5.
Pappenheimer et al. (1997) Absorption and Excretion of Undegradable Peptides: Rols of Lipid Solubility and Net Charge. J Pharmacol Exp Ther. 280(1):292-300.
Pardridge et al. (1995) Vector-mediated delivery of a polyamide ("peptide") nucleic acid analogue through the blood-brain barrier in vivo. Proc Natl Acad Sci USA. 92(12):5592-6.
Parhami, F. et al. (1997) Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol. 17(4): 680-7.
Pasceri et al. (2000) Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 102:2165-8.
Pasceri et al. (2001) Modulation of Creactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs, Circulation. 103:2531-4.
Pasqui, A.L. et al. (2005) Structural and functional abnormality of systemic microvessels in cardiac syndrome X. Nutr Metab Cardiovasc Dis. 15(1): 56-64.
Pastan et al. (1988) A retrovirus carrying an MDR1 cDNA confers multidrug resistance and polarized expression of P-glycoprotein in MDCK cells. Proc Natl Acad Sci USA. 85: 4486.
Pászty et al. (1994) Apolipoprotein Al Transgene Corrects Apolipoprotein E Deficiency-induced Atherosclerosis in Mice. J Clin Invest. 94:899-903.
Patent Examination Report No. 1 dated Apr. 15, 2016 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Patent Examination Report No. 1 issued on Apr. 15, 2016 by the Intellectual Property Office of Australia for Patent Application No. AU 2014239186, which was filed on Mar. 14, 2014 (Inventor—Anatharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Pillot et al. (1997) The 118-135 peptide of the human prion protein forms amloid fibrils and induces liposome fusion. J Mol Biol. 274: 381-93.
Pilone (2000) D-amino acid oxidase: new findings. Cell Mol Life Sci. 57:1732-47.
Plump et al. (1994) Human apolipoprotein A-I gene expression increases high density lipoprotein and suppresses stherosclerosis in the apolipoprotein E-deficient mouse. Proc Natl Acad Sci USA. 91:9607-11.
Pohle, K. et al. (2001) Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation. 104(16): 1927-32.
Posttranslational Covalent Modification of Proteins, B.C. Johnson, Ed., Academic Press, New York, pp. 1-12 (1983).
Preliminary Amendment filed Mar. 12, 2010 filed with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (8 pages).
Preliminary Amendment filed May 14, 2004 for U.S. Appl. No. 10/712,447 (7 pages).
Preliminary Amendment filed Nov. 13, 2003 for U.S. Appl. No. 10/712,447 (6 pages).
Preliminary Amendment filed on Aug. 25, 2015 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (5 pages).
Preliminary Amendment filed on Jul. 14, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Preliminary Amendment filed on Jul. 14, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Preliminary Amendment filed on Jul. 6, 2010 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (3 pages).
Preliminary Amendment filed on Jul. 6, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Preliminary Amendment filed on Jul. 6, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (3 pages).
Preliminary Amendment filed on Mar. 16, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Preliminary Amendment filed on Mar. 16, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (5 pages).
Preliminary Amendment filed on Sep. 11, 2015 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al; Applicant-UAB Research Foundation) (3 pages).
Presta (1992) Antibody engineering. Curr Opin Struct Biol. 2:593-6.
Presta (1992) Antibody engineering. Curr Opin Struct Biol. 2:593-6. Purdue News (2000) ‘Microspheres’ Offer Promise for Oral Drug Delivery (pp. 1-3).
Purdue News (1997) New Oral Insulin Delivery System Shows Promise (pp. 1-3).
Purdue News (2000) ‘Microspheres’ Offer Promise for Oral Drug Delivery (pp. 1-3).
Purdue News (2000) ‘Migrosphergs’ Offer Promise for Oral Drug Delivery (pp. 1-3).
Quyyumi, A.A. (1998) Endothelial Function in Health and Disease: New Insights into the Genesis of Cardiovascular Disease. Am J Med. 105:32S-9S.
Rader, D.J. (2003) Regulation of Reverse Cholesterol Transport and Clinical Implications. Am J Cardiol. 92:42J-9J.
Ragot, T. et al. (1993) Replication-defective recombinant adenovirus expressing the Epstein-Barr virus (EBV) envelope glycoprotein gp340]220 induces protective immunity against EBV-induced lymphomas in the cottontop tamarin. J Gen Virol. 74:501-7.
Raha et al. (1988) KRDS a tetra peptide derived from lactotransferrin inhibits binding of monoclonal antibody against glycoprotein Iib-IIIa on ADP-stimulated platelets and megakaryocytes. Blood. 72: 172-8.
Raha et al. (1988) KRDS a tetra peptide derived from lactotransferrin inhibits binding of monoclonal antibody against glycoprotein lib-llla on ADP-stimulated platelets and megakaryocytes. Blood. 72: 172-8.
Raj arathnam et al. (1994) 1H NMR studies of interleukin 8 analogs: characterization of the domains essential for function. Biochemistry. 33:6623-30.
Rajashree, S. and Puvanakrishnan, R. (1996) Alterations in certain lysosomal glycohydrolases and cathepsins in rats on dexamethasone administration. Mol Cell Biochem. 154(2):165-70.
Rajashree, S. and Puvanakrishnan, R. (1998) Dexamethasone induced alterations in enzymatic and nonenzymatic antioxidant status in heart and kidney of rats. Mol Cell Biochem. 181(1-2):77-85.
Rajashree, S. and Puvanakrishnan, R. (1999) Dexamethasone induced alterations in the levels of proteases involved in blood pressure homeostasis and blood coagulation in rats. Mol Cell Biochem. 197(1-2):203-8.
Rall, S. C., Jr. et al., Structural basis for Receptor Binding Heterogeneity of Apolipoprotein E from Type III Hyperlipoproteinemic Subjects. Proc Natl Acad Sci USA. 1982; 79(15):4696-700.
Ram et al. (1993) In Situ Retroviral-mediated Gene Transfer for the Treatment of Brain Tumors in Rats. Cancer Res. 53:83-8.
Ramesh et al. (1998) A novel surface-active peptide derivative exhibits in vitro inhibition of platelet aggregation. Peptides. 19:1695-702.
Ramesh et al. (1998) Effect of a novel tetrapeptide derivative in a model of isoproterenol induced myocardial necrosis. Mol Cell Biochem. 187(1-2):173-82.
Ramprasad et al. (2002) Sustained-delivery of an apolipoproteinE—peptidomimetic using multivesicular liposomes lowers serum cholesterol levels. J Controlled Release. 79:207-18.
Ranganathan, D. et al. (2000) Channel-Forming Self-Assembling, Bishelical Amphiphilic Peptides: Design, Synthesis and Crystal Structure of Py (Aibn)2, n=2, 3, 4. J Peptide Res. 56(6): 416-26.
Rapp, J.H. et al. (1994) Triglyceride rich lipoproteins isolated by selected affinity antiapolipoprotein B immunosorption from human atherosclerotic plaque. Atheroscler Thromb. 14:1767-74.
Raussens et al. (2002) NMR Structure and Dynamic of a Receptor-active Apolipoprotein E Peptide. J Biol Chem. 277: 29172-80.
RCE/Response to Final Office Action filed Aug. 15, 2005 for U.S. Appl. No. 10/273,386.
RCE/Response to Final Office Action filed Jul. 13, 2009 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
RCE/Response to Final Office Action filed Jul. 13, 2009 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
RCE/Response to Final Office Action filed Nov. 15, 2004 for U.S. Appl. No. 09/896,841 (17 pages).
RCE/Response to Final Office Action filed Oct. 18, 2006 for U.S. Appl. No. 10/423,830.
RCE/Response to Final Office Action filed Oct. 7, 2005 for U.S. Appl. No. 10/187,215.
Reape and Groot (1999) Chemokines and atherosclerosis. Atherosclerosis. 147:213-25.
Recent Developments in the Synthesis of Fatty Acid Derivatives. Eds. Knothe, G. and Derksen, J.T.B., AOCS Press 1999; ISBN: 1-893997-00-6.
Reddy et al. (2001) Human paraoxonase-3 is an HDLassociated enzyme with biological activity similar to paraoxonase-1 protein but is not regulated by oxidized lipids. Arterioscler Thromb Vasc Biol. 21:542-7.
Reddy et al. (2004) Potential role for mitogen-activated protein kinase phosphatase-1 in the development of atherosclerotic lesions in mouse models. Arterioscler Thromb Vasc Biol. 24:1676-81.
Remaley et al. (2003) Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway. J Lipid Res. 44:828-36.
Rembold, C.M. (2004) Combination Therapy of Dyslipidemia in Non-Insulin-Dependent Diabetes Mellitus and the Metabolic Syndrome. Curr Diab Rep. 4(5): 330-4.
Remington: The Science and Practice of Pharmacy, 19th ed., A.R. Gennaro, Ed., Mack Publishing Company, Easton, PA (1995).
Rencurel, F. et al. (2006) Stimulation of AMP-activated protein kinase is essential for the induction of drug metabolizing enzymes by Phenobarbital in human and mouse liver. Mol Pharmacol. 70:1925-34.
Rensen, P.C., and van Berkel, T.J. (1996) Apolipoprotein E effectively inhibits lipoprotein lipase-mediated lipolysis of chylomicronlike triglyceride-rich lipid emulsions in vitro and in vivo. J Biol Chem. 271:14791-9.
Request for Certificate of Correction filed Aug. 3, 2009 for U.S. Appl. No. 10/712,447 (4 pages).
Response After Final Office Action filed on Jul. 13, 2015 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (11 pages).
Response After Final Office Action filed on Oct. 09, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Response After Final Office Action filed on Oct. 9, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Response after Non-Final Office Action filed Mar. 12, 2008 for U.S. Appl. No. 10/712,447 (14 pages).
Response to Advisory Action and Final Office Action filed Sep. 4, 2007 for U.S. Appl. No. 10/712,447 (16 pages).
Response to Ex Parte Quayle Action filed Oct. 14, 2009 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Response to Ex Parte Quayle Action filed Oct. 14, 2009 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Response to Examination Report filed Dec. 23, 2008 for New Zealand Application No. 541504 (6 pages).
Response to Examination Report filed Jul. 16, 2008 for New Zealand Application No. 541504 (18 pages).
Response to Examination Report filed Mar. 18, 2009 for New Zealand Application No. 541504 (3 pages).
Response to Final Office Action and Request for Continued Examination filed on Sep. 19, 2017 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (13 pages).
Response to Final Office Action and Request for Continued Examination filed on Sep. 19, 2017 with U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah et al.; Applicant—UAB Research Foundation) (13 pages).
Response to Final Office Action filed Jul. 3, 2006 for U.S. Appl. No. 10/273,386.
Response to Final Office Action filed Jul. 31, 2007 for U.S. Appl. No. 10/712,447(15 pages).
Response to Final Office Action filed on May 9, 2013 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (18 pages).
Response to Final Office Action filed Sep. 28, 2010 for U.S. Appl. No. 11/405,601 (20 pages).
Response to Non-Final Office Action filed Apr. 23, 2004 for U.S. Appl. No. 09/896,841 (23 pages).
Response to Non-Final Office Action filed Dec. 21, 2004 for U.S. Appl. No. 10/273,386.
Response to Non-Final Office Action filed Feb. 28, 2005 for U.S. Appl. No. 10/187,215.
Response to Non-Final Office Action filed Jan. 20, 2006 for U.S. Appl. No. 10/273,386.
Response to Non-Final Office Action filed Jul. 12, 2004 for U.S. Appl. No. 10/187,215 (18 pages).
Response to Non-Final Office Action filed Jul. 17, 2008 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Response to Non-Final Office Action filed Jul. 17, 2008 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Response to Non-Final Office Action filed Mar. 20, 2006 for U.S. Appl. No. 10/187,215.
Response to Non-Final Office Action filed May 27, 2003 for U.S. Appl. No. 09/645,454.
Response to Non-Final Office Action filed Nov. 29, 2006 for U.S. Appl. No. 10/712,447 (21 pages).
Response to Non-Final Office Action filed Oct. 19, 2005 for U.S. Appl. No. 10/423,830.
Response to Non-Final Office Action filed on Apr. 10, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (15 pages).
Response to Non-Final Office Action filed on Apr. 10, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (15 pages).
Response to Non-Final Office Action filed on Aug. 14, 2018 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 17, 2016 (Inventor—G.M. Anantharamaiah, et al.; Applicant—UAB Research Foundation) (12 pages).
Response to Non-Final Office Action filed on Jan. 12, 2015 with the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (17 pages).
Response to Non-Final Office Action filed on Jan. 15, 2015 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (13 pages).
Response to Non-Final Office Action filed on Jan. 4, 2017 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (10 pages).
Response to Non-Final Office Action filed on Mar. 25, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Appliant—UAB research Foudation) (14 pages).
Response to Non-Final Office Action filed on Mar. 25, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (14 pages).
Response to Non-Final Office Action filed on Mar. 26, 2013 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (11 pages).
Response to Non-Final Office Action filed on Mar. 26, 2013 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (11 pages).
Response to Non-Final Office Action filed on Nov. 1, 2011 with the U.S. Patent and Trademark Office for U.S. App. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Response to Non-Final Office Action filed on Nov. 1, 2011 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Response to Non-Final Office Action filed on Oct. 10, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (10 pages).
Response to Non-Final Office Action filed on Oct. 10, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (10 pages).
Response to Non-Final Office Action filed on Oct. 29, 2012 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (16 pages).
Response to Non-Final Office Action filed Sep. 3, 2008 for U.S. Appl. No. 10/712,447 (9 pages).
Response to Non-Final Rejection filed Oct. 9, 2009 for U.S. Appl. No. 11/405,601 (17 pages).
Response to Office Action filed Feb. 10, 2010 for Canadian Application No. 2,514,303 (19 pages).
Response to Office Action filed Mar. 29, 2011 for Canadian Application No. 2,514,303 (11 pages).
Response to Restriction Reqirement filed Nov. 19, 2003 for U.S. Appl. No. 10/187,215 (17 pages).
Response to Restriction Requirement filed Aug. 25, 2003 for U.S. Appl. No. 09/896,841 (16 pages).
Response to Restriction Requirement filed Dec. 12, 2002 for U.S. Appl. No. 09/645,454.
Response to Restriction Requirement filed Jul. 25, 2008 for U.S. Appl. No. 11/405,601 (8 pages).
Response to Restriction Requirement filed Mar. 1, 2005 for U.S. Appl. No. 10/423,830.
Response to Restriction Requirement filed Mar. 16, 2006 for U.S. Appl. No. 10/712,447 (10 pages).
Response to Restriction Requirement filed Mar. 17, 2009 for U.S. Appl. No. 11/405,601 (5 pages).
Response to Restriction Requirement filed May 3, 2004 for U.S. Appl. No. 10/273,386.
Response to Restriction Requirement filed Nov. 23, 2007 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Response to Restriction Requirement filed Nov. 23, 2007 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Response to Restriction Requirement filed on Apr. 25, 2014 with the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (9 pages).
Response to Restriction Requirement filed on Feb. 5, 2016 with the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (4 pages).
Response to Restriction Requirement filed on Jul. 23, 2013 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Response to Restriction Requirement filed on May 16, 2012 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (9 pages).
Response to Restriction Requirement filed on May 22, 2013 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, filed Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (11 pages).
Response to Restriction Requirement filed on May 22, 2013 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, which was filed on Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (11 pages).
Response to Restriction Requirement filed on Sep. 1, 2017 with the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant-UAB Research Foundation) (5 pages).
Response to Restriction Requirement filed on Sep. 12, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Response to Restriction Requirement filed on Sep. 12, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Response to Restriction Requirement filed on Sep. 27, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Invento—Anantharamaiah et al.; Applicant—UAB research Foundation).
Response to Restriction Requirement filed on Sep. 27, 2010 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation).
Restriction Requirement dated Apr. 16, 2012 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applican—UAB Research Foundation) (7 pages).
Restriction Requirement dated Aug. 12, 2010 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (7 pages).
Restriction Requirement dated Aug. 21, 2007 for U.S. Appl. No. 11/407,390, filed Apr. 18, 2006 and granted as U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.).
Restriction Requirement dated Dec. 18, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement dated Feb. 1, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Restriction Requirement dated Feb. 16, 2006 for U.S. Appl. No. 10/712,447 (9 pages).
Restriction Requirement dated Feb. 19, 2004 for U.S. Appl. No. 10/273,386.
Restriction Requirement dated Feb. 20, 2003 for U.S. Appl. No. 09/896,841 (4 pages).
Restriction Requirement dated Feb. 7, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, filed Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applican—UAB Research Foundation) (11 pages).
Restriction Requirement dated Jul. 15, 2003 for U.S. Appl. No. 10/187,215 (4 pages).
Restriction Requirement dated Jul. 9, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, filed Mar. 22, 2010 and granted as U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Restriction Requirement dated Jun. 26, 2008 for U.S. Appl. No. 11/405,601 (11 pages).
Restriction Requirement dated Mar. 6, 2017 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement dated Nov. 27, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (7 pages).
Restriction Requirement dated Nov. 9, 2004 for U.S. Appl. No. 10/423,830.
Restriction Requirement dated Oct. 14, 2005 for U.S. Appl. No. 10/712,447 (9 pages).
Restriction Requirement dated Sep. 12, 2002 for U.S. Appl. No. 09/645,454.
Restriction Requirement issued Aug. 21, 2007 for U.S. Appl. No. 11/407,390, which was filed on Apr. 18, 2006 and now U.S. Pat. No. 7,723,303 on May 25, 2010 (Inventor—Fogelman et al.;).
Restriction Requirement issued Feb. 16, 2006 for U.S. Appl. No. 10/712,447 (9 pages).
Restriction Requirement issued Feb. 19, 2004 for U.S. Appl. No. 10/273,386.
Restriction Requirement issued Feb. 20, 2003 for U.S. Appl. No. 09/896,841 (4 pages).
Restriction Requirement issued Jul. 15, 2003 for U.S. Appl. No. 10/187,215 (4 pages).
Restriction Requirement issued Jun. 26, 2008 for U.S. Appl. No. 11/405,601 (11 pages).
Restriction Requirement issued Nov. 9, 2004 for U.S. Appl. No. 10/423,830.
Restriction Requirement issued Oct. 14, 2005 for U.S. Appl. No. 10/712,447 (9 pages).
Restriction Requirement issued on Apr. 16, 2012 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 12/675,089, filed Apr. 21, 2010 and published as US 2010/0298215 on Nov. 25, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement issued on Aug. 12, 2010 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (7 pages).
Restriction Requirement issued on Dec. 18, 2015 by the U.S. Patent and Trademark Office for U.S. Appl. No. 14/770,270, filed Aug. 25, 2015 and published as US 2016/0002315 on Jan. 7, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement issued on Feb. 1, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/865,957, filed Oct. 15, 2010 and published as US 2011/0182992 on Jul. 28, 2011 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Restriction Requirement issued on Feb. 7, 2013 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 13/429,022, which was filed on Mar. 23, 2012 and published as US 2012/0245101 on Sep. 27, 2012 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (11 pages).
Restriction Requirement issued on Jul. 9, 2012 by the U.S. Patent and Trademark Office for U.S. Appl. No. 12/675,073, which was filed on Mar. 22, 2010 and now U.S. Pat. No. 8,557,767 on Oct. 15, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Restriction Requirement issued on Mar. 6, 2017 by the U.S. Patent and Trademark Office for for U.S. Appl. No. 14/851,622, filed Sep. 11, 2015 and published as US 2016/0151455 on Jun. 2, 2016 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (7 pages).
Restriction Requirement issued on Nov. 27, 2013 by the U.S. Patent and Trademark Office for U.S. Appl. No. 13/804,161, filed Mar. 14, 2013 and published as US 2013/0295042 on Nov. 7, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (7 pages).
Restriction Requirement issued Sep. 12, 2002 for U.S. Appl. No. 09/645,454.
Ridker, P. M. (2002) On evolutionary biology, inflammation, infection, and the causes of atherosclerosis. Circulation. 105:2-4.
Roessler, J. et al. (1993) Adenoviral-mediated gene transfer to rabbit synovium in vivo. J Clin Invest. 92:1085-92.
Rogers, et al. (1998) The lipid-free structure of apolipoprotein A-I: effects of aminoterminal deletions. Biochemistry. 37:11714-25.
Roher et al. (1993) β-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: Implications for the pathology of Alzheimer disease. Proc Natl Acad Sci USA. 90:10836-40.
Rohlmann, A. et al. (1998) Inducible Inactivation of Hepatic LRP Gene by Cre-mediated Recombination Confirms Role of LRP in Clearance of Chylomicron Remnants. J Clin Invest. 101:689-95.
Romá´n et al. (2002) Subcortical ischaemic vascular dementia. Lancet Neurol. 1:426-36.
Rong et al. (2001) Elevating high-density lipoprotein cholesterol in apolipoprotein E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content. Circulation. 104:2447-52.
Roscoe, H.G. and A.W. Vogel (1968) Lipid Changes in the Eye Concomitant with the Development of Atherosclerosis in the Aorta in the Rabbit. Circ Res. 23(5): 633-43.
Rose, D.J. (1993) Characterization of antisense binding properties of peptide nucleic acids by capillary gel electrophoresis. Anal Chem. 65(24):3545-9.
Rubin et al. (1991) Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. Nature. 353:265-7.
Sabbatini et al. (2001) Microanatomical changes of intracerebral arteries in spontaneously hypertensive rats: a model of cerebrovascular disease of the elderly. Mech Aging Dev. 122:1257-68.
Sabbatini et al. (2001) Microanatomical changes of intracerebral arteries in spontaneously hypertensive rats: a model of cerebrovasular disease of the elderly. Mech Aging Dev. 122:1257-68.
Saison-Behmoaras et al. (1991) Short modified antisense oligonucleotides directed against Ha-ras point mutation induce selective cleavage of the mRNA and inhibit T24 cells proliferation. EMBO J. 10:1111-8.
Sandana Mala, J.G. et al. (2001) Strain improvement of Aspergillus niger for enhanced lipase production. J Gen Appl Microbiol. 47 (4):181-6.
Sattler, W. and Stocker, R. (1993) Greater selective uptake by Hep G2 cells of highdensity lipoprotein cholesteryl ester hydroperoxides than of unoxidized cholesterylesters. Biochem J. 294:771-8.
Schmitz-Peiffer C. (2000) Signaling aspects of insulin resistance in skeletal muscle: mechanisms induced by lipid oversupply. Cell Signal. 12(9-10):583-94.
Schnölzer et al. (1992) Constructing proteins by dovetailing unprotected synthetic peptides: backbone-engineered HIV protease. Science. 256: 221.
Schönbeck, U. and Libby, P. (2004) Inflamation, Immunity, and HMG-COA Reductase Inhibitors, Statins as Anti inflammatory Agents? Circulation. 109(21 Suppl 1):II18-26.
Schonfeld et al. (1979) Lipolysis produces changes in the immunoreactivity and cell reactivity of very low density lipoproteins. J Clin Invest. 64:1288-97.
Segrest et al, (1974) A Molecular Theory of Lipid-Protein Interaction in the Plasma Lipoproteins. FEBS Left. 38: 247-253.
Segrest et al. (1990) Amphipathic Helix Motif: Classes and Properties. Proteins: Struct, Funct. Genet. 8:103-17.
Segrest et al. (1994) ApoB-100 has a pentapartite structure composed of three amphipathic alpha-helical domains alternating with two amphipathic beta-strand domains. Detection by the computer program LOCATE. Arterioscler Thromb. 14:1674-85.
Segrest et al. (1998) Apolipoprotein B-100: conservation of lipidassociating amphipathic secondary structural motifs in nine species of vertebrates. J Lipid Res. 39:85-102.
Segrest, J.P. et al., Structure of Apolipoproteins B-100 in Low Density Lipoproteins. J Lipid Res. 2001; 42(9):1346-67.
Segrest, J.P. et al., The Amphipathic Helix in the Exchangeable Apolipoproteins: A Review of Secondary Structure and Function. J Lipid Res. 1992; 33(2):141-66.
Senior (1999) New options developed for needle-free drug delivery. Lancet. 1998:354:1102.
Seth, et al. (1984) Evidence that the Penton Base of Adenovirus is Involved in Potentiation of Toxicity of Pseudomonas Exotoxin Conjugated to Epidermal Growth Factor. Mol Cell Biol. 4:1528-33.
Seth, et al. (1984) Role of a low-pH environment in adenovirus enhancement of the toxicity of a Pseudomonas exotoxin-epidermal growth factor conjugate. J Virol. 51:650-5.
Shah et al. (1998) Effects of recombinant apolipoprotein A-I(Mi.lano) on aortic atherosclerosis in apolipoprotein E-deficient mice. Circulation. 97(8):780-5.
Shah et al. (2001) High-dose recombinant apolipoproteins A-Imilano mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophase content in apolipoprotein Edeficient mice: potential implications ofr acute plaque stabilization. Circulation. 103:3047-50.
Shah, P.K. et al. (2005) Apolipoprotein A-I mimetic peptides: potential role in atherosclerosis management. Trends Cardiovasc Med. 15:291-6.
Sharp, R.J. et al. (2004) Structural Features of Apolipoprotein B Synthetic Peptides that Inhibit Lipoprotein(a) Assembly. J Lipid Res. 45(12):2227-34.
Shea et al. (1990) Synthesis, hybridization properties and antiviral activity of lipid-oligodeoxynucleotide conjugates. Nucl Acids Res. 18:3777-83.
Shen, B.W. et al. (1977) Structure of human serum lipoproteins inferred from compositional analysis. Proc Natl Acad Sci USA. 74:837-41.
Shih et al. (1999) Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating beta integrin. J Clin Invest. 103:613-25.
Shih et al. (2000) Combined serum paraoxonase/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem. 275:17527-35.
Shimano, H. et al., Plasma Lipoprotein Metabolism in Transgenic Mice Overexpressing Apolipoprotein E. Accelerated Clearance of Lipoproteins Containing Apolipoprotein B. J Clin Invest. 1992; 90(5):2084-91.
Shishehbor et al. (2003) Association of nitrotyrosine levels with cardiovascular disease and modulation by statin therapy. JAMA. 289(13):1675-80.
Silkensen et al. (1999) Identification of clusterin sequences mediating renal tubular cell interactions. J Peptide Res. 54:449-47.
Singh et al. (2000) Innate defences against viremia. Rev Med Virol. 10:395-403.
Sonntag et al. (1997) Decreases in Cerebral Microvasculature with Age are Associated with the Decline in Growth Hormone and Insulin-Like Growth Factor 1. Endocrinology. 138(8): 3515-20.
Sorescu et al. (2001) NAD(P)H oxidases and their relevance to atherosclerosis. Trends Cardiovasc Med. 11:124-31.
Spangenberg, J. and L.K. Curtiss, Influence of Macrophage-Derived Apolipoprotein E on Plasma Lipoprotein Distribution of Apolipoprotein A-I in Apoprotein E-Deficient Mice. Biochim Biophys Acta. 1997; 1349:109-21.
Sparrow, C.P. et al. (2002) A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABC A1-mRNA and stimulating cholesterol efflux. J Biol Chem. 277:10021-7.
Sparrow, C.P. et al. (2002) A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABC Al-mRNA and stimulating cholesterol efflux. J Biol Chem. 277:10021-7.
Sparrow, J.T. et al., Apolipoprotein E: Phospholipid Binding Studies with Synthetic Peptides from the Carboxyl Terminus. Biochemistry. 1992; 31(4):1065-8.
Spatola Vega Data 1(3) Peptide Backbone Modifications (1982) (general review).
Spatola, A.F., Structure-Activity Relationships of Enkephalins Containing Serially Replaced Thiomethylene Amide Bond Surrogates. Life Sci. 1986; 38(14):1243-9.
Spatola, Chemistry and Biochemistry of Amino Acids, Peptides, and Proteins. B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983).
Spieker et al. (2002) High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation. 105:1399-402.
Sprecher et al. (1993) The Low HDL Cholesterol/High Triglyceride Trait. Arterioscler Thromb. 13: 495-504.
Springer, T.A. (1990) Adhesion receptors of the immune system. Nature. 346:425-34.
Srinivas et al. (1990) Antivrial Effects of Apolipoprotein A-I and Its Synthetic Amphipathic Peptide Analogs. Virology. 176:48-57.
Stannard et al. (2001) Inability of plasma high-density lipoproteins to inhibit cell adhesion molecule expression in human coronary artery endothelial cells. Atherosclerosis. 154:31-8.
Steinberg, D. and J.L. Witztum, Inhibition of PCSK9: A Powerful Weapon for Achieving Ideal LDL Cholesterol Levels. Proc Natl Acad Sci USA. 2009; 106(24):9546-7.
Steinberg, D. et al., Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia. Circulation. 2008; 118(6):672-7.
Steplewski et al. (1985) Isolation and characterization of anti-monosialoganglioside monoclonal antibody 19-9 class-switch variants. Proc Natl Acad Sci USA. 82: 8653.
Structure and Molecular Properties 2nd ed., T.E. Creighton, W.H. Freeman and Company, New York (1993).
Sugatani et al. (1996) High-density lipoprotein inhibits the synthesis of platelet-activating factor in human vascular endothelial cells. J Lipid Mediators Cell Signal. 13:73-88.
Sumitra et al. (2001) Experimental myocardial necrosis in rats: role of arjunolic acid on platelet aggregation, coagulation and antioxidant status. Mol Cell Biochem. 224(1-2): 135-42.
Supplemental Response to Non-Final Office Action filed on Dec. 5, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and granted as U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Supplemental Response to Non-Final Office Action filed on Dec. 5, 2012 with the U.S. Patent and Trademark Office for U.S. Appl. No. 12/027,728, filed Feb. 7, 2008 and now U.S. Pat. No. 8,568,766 on Oct. 29, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (8 pages).
Supplementary European Search Report dated Apr. 8, 2011 by the European Patent Office for European Patent Application No. 08798802.8, which was filed on Aug. 27, 2008 and granted as 2195331 on Nov. 20, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Supplementary European Search Report dated Apr. 8, 2011 by the European Patent Office for European Patent Application No. 08829135.6, which was filed on Mar. 26, 2010 and published as 2195340 on Jun. 16, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Supplementary European Search Report dated Feb. 2, 2018 by the European Patent Office for Patent Application No. 15826625.4, which was filed on Jul. 20, 2015 and published as EP 3189069 on Jul. 12, 2017 (Inventor—Anatharamaiah et al.; Applicant—UAB Reasearch Foundation et al.) (10 pages).
Supplementary European Search Report dated Nov. 29, 2011 by the European Patent Office for patent application No. 03783409.0, which was filed on Nov. 13, 2003 and published as 1599173 on Nov. 30, 2005 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (3 pages).
Supplementary European Search Report issued on Apr. 8, 2011 by the European Patent Office for European Patent Application No. 08798802.8, which was filed on Aug. 27, 2008 and granted as 2195331 on Nov. 20, 2013 (Inventor—Anantharamaiah et al.; Applicant—UAB research Foundation) (6 pages).
Supplementary European Search Report issued on Apr. 8, 2011 by the European Patent Office for European Patent Application No. 08829135.6, which was filed on Mar. 26, 2010 and published as 2195340 on Jun. 16, 2010 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation) (6 pages).
Supplementary European Search Report issued on Feb. 2, 2018 by the European Patent Office for Patent Application No. 15826625.4, which was filed on Jul. 20, 2015 and published as EP 3189069 on Jul. 12, 2017 (Inventor—Anatharamaiah et al.; Applicant—UAB Reasearch Foundation et al.) (10 pages).
Supplementary European Search Report mailed on Nov. 29, 2011 by the European Patent Office for patent application No. 03783409.0, which was filed on Nov. 13, 2003 and published as 1599173 on Nov. 30, 2005 (Inventor—Gattadahalli et al.; Applicant—UAB research Foundation) (3 pages).
Suresh, R. et al. (1992) Alterations in human gingival glycosaminoglycan pattern in inflammation and in phenytoin induced overgrowth. Mol Cell Biochem. 115(2):149-54.
Svensson, U. (1985) Role of vesicles during adenovirus 2 internalization into HeLa cells. J Virology. 55:442-9.
Swain, J. et al. (1995) Prooxidant iron and copper, with ferroxidase and xanthine oxidase activities in human atherosclerotic material. FEBS Lett. 368(3):513-5.
Swarnakar et al. (2001) The apolipoprotein E-dependent low density lipoprotein cholesteryl ester selective uptake pathway in murine adrenocortical cells involves chondroitin sulfate proteoglycans and an alpha 2-macroglobulin receptor. J Biol Chem. 276:21121-6.
Swift, L.L. et al. (2001) A recycling pathway for resecretion of internalized apolipoprotein E in liver cells. J Biol Chem. 276:22965-70.
Takahashi, S.Y. et al. (1992) Rabbit very low density lipoprotein receptor-a low density receptor like protein with distinct ligand specificity. Proc Natl Acad Sci USA. 89: 9252-6.
Tam et al. (1997) Interaction of a recombinant form of apolipoprotein[a] with human fibroblasts and with the human hepatoma cell line HepG2. J Lipid Res. 37(3): 518-33.
Tam, S.P. et al., Interaction of a Recombinant Form of Apolipoprotein[a] with Human Fibroblasts and with Human Hepatoma Cell Ilne HepG2. J Lipid Res. 1997; 37(3):518-33.
Tan et al. (1997) A Novel, highly Efficient Peptide-HLA Class TH:ca Binding Assay using unfolded heavy change molecules: Identification of HIV-1 Derived Peptides that Bind to FILA-A* 0201 and HLA-A* 0301. J Immunol Methods. 205:201-9.
Terminal Disclaimer accepted Feb. 12, 2009 for U.S. Appl. No. 10/712,447 (1 page).
Terminal Disclaimer filed Sep. 3, 2008 for U.S. Appl. No. 10/712,447 (3 pages).
Thomas, E.C. (1999) Brain macrophages: on the role of pericytes and perivascular cells. Brain Res Rev. 31: 42-57.
Throngate, F.E. et al. (2000) Low levels of extrahepatic nonmacrophage ApoE inhibit atherosclerosis without correcting hypercholesterolemia in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 20:1939-45.
Tian et al. (2002) Structure-affinity relationships in the gp41 ELDKWA epitope for the HIV-1 neutralizing monoclonal antibody 2F5: effects of side-chain and backbone modifications and conformational constraints. J Peptide Res. 59:264-76.
Toyoda, K. et al (1997) Effect of Aging on Regulation of Brain Stem Circulation During hypotension. J Cerebral Blood Flow Metab. 17(6): 680-5.
Tracy, M.A., Development and Scale-up of a Microsphere Protein Delivery System. Biotechnol Prog. 1998; 14(1):108-15.
Transmittal of the International Search Report and Written Opinion dated Mar. 9, 2009 by the International Searching Authority for International Patent Application No. PCT/US2008/074470, which was filed on Aug. 27, 2008 and published as WO 2009/032693 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation).
Transmittal of the International Search Report and Written Opinion mailed on Mar. 9, 2009 by the International Searching Authority for International Patent Application No. PCT/US2008/074470, which was filed on Aug. 27, 2008 and published as WO 2009/032693 on Mar. 12, 2009 (Inventor—Anantharamaiah et al.; Applicant—UAB Research Foundation).
Triaggiai et al. (2004) An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat Med. 10(8):871-5.
Tsai et al. (1998) D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 44: 1081-9.
Tsao et al. (2001) Hibernation-induction Peptide and Cell Death: [D-Ala2, D-Leulenkephalin Blocks Bax-related Apoptotic Processes. Eur J Pharmacol. 428:149-51.
Tsimikas et al. (2001) Measuring Circulating Oxidized Low-Density Lipoprotein to Evaluate Coronary Risk. Circulation 103:1930-2.
Tward et al. (2002) Decreased atherosclerotic lesion formation in human serum paraoxonase transgenic mice. Circulation. 106:484-90.
Tytler et al. (1993) Reciprocal effects of apolipoprotein and lytic peptide analogs on membranes. Cross-sectional molecular shapes of amphipathic alpha helixes control membrane stability. J Biol Chem. 268: 2212-8.
U.S. Appl. No. 15/329,735, filed Jan. 27, 2017, Anantharamaiah.
U.S. Appl. No. 62/031,585, filed Jul. 31, 2014, Anantharamaiah.
Valabhji, J. et al. (2001) High-density lipoprotein composition and paraoxonase activity in Type I diabetes. Clin Sci (Lond). 101(6):659-70.
Van Leeuwen, R. et al. (2003) Epidemiology of age-related maculopathy: a review. Eur J Epidemiol. (9):845-54.
Van Lenten et al. (1995) Anti-inflammatory HDL Becomes Pro-inflammatory during the Acute Phase Response. J Clin Invest. 96:2758-67.
Van Lenten et al. (2002) Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide. Circulation. 106:1127-32.
Van Lenten, B.J. et al. (2001) High-density lipoprotein loses its anti-inflammatory properties during acute influenza A infection, Circulation. 103:2283-8.
Van Lenton et al. (2004) D-4F an ApoA-I mimetic peptide inhibits the inflammatory response induced by influenza A infection of human type II pneumocytes. Circulation. 110:3252-8.
Van Velzen et al., Imagining of Atherosclerosis: Invasive and Noninvasive Techniques. Hellenic J Cardiol. 2009; 50:245-63.
Varga et al. (1991) Infectious entry pathway of adenovirus type 2. J Virol. 65:6061-70.
Vaughan, C.J. et al., the Evolving Role of Statins in the Management of Atherosclrosis. J Am Coll Cardiol. 2000; 35(1):1-10.
Venugopal et al. (2002) Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 106:1439-41.
Verhoeyen et al. (1988) Reshaping human antibodies: grafting an antilysozyme activity. Science. 239:1534-6.
Vinters et al. (1998) Secondary microvascular degeneration in amyloid angiopathy of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). Acta Neuropathol. 95:235-44.
Vitamins, or the Combination for the Prevention of Coronary Disease. N Engl J Med. 345(22):1583-92.
Vovenko, E. (1999) Distribution of oxygen tension on the surface of arterioles, capillaries and venules of brain cortex and in tissue in normoxia; an experimental study on rats. Eur J Physiol. 437:617-23.
Wake, A.K. et al. (2008) Apolipoprotein A-1 mimetic peptide retains function after oxidant exposure. Proc ASME 2008 Summer Bioenginerring Conference (Marco Island, Florida), Jun. 25-29, 2008, SBC2008-189660.
Walpola et al. (1995) Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress. Arterioscler Thromb Vasc Biol. 15:2-10.
Watson et al. (1995) Effect of platelet activating factor-acetylhydrolase on the formation and action of minimally oxidized-low gensitylipoprotein. J Clin Invest. 95:774-82.
Watson et al. (1995) Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein. J Clin Invest. 96:2882-91.
Watts et al. (1998) Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: a hypothesis. Atherosclerosis. 141:17-30.
Weers, P.M. et al. (2001) Modulation of the lipid binding properties of the N-terminal domain of human apolipoprotein E3. Eur J Biochem. 268(13): 3728-35.
Wei et al. (1998) Antioxidants Inhibit ATP-Sensitive Potassium Channels in Cerebral Arterioles. Stroke. 29: 817-23.
White, C. R. et al. (1994) Superoxide and peroxynitrite in atherosclerosis. Proc Natl Acad Sci USA. 91:1044-8.
White, C.R. et al. (1996) Circulating plasma xanthine oxidase contributes to vascular dysfunction in hypercholesterolemic rabbits. Proc Natl Acad Sci USA. 93:8745-9.
Wickham et al. (1993) Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell. 73:309-19.
Wilson, C. et al., Three-Dimensional Structure of the LDL receptor-Binding Domain of Human Apolipoprotein E. Science. 1991; 252(5014):1817-22.
Witztum, J.L. et al. (1991) Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 88:1785-92.
Wolff, J.A. et al. (1990) Direct gene transfer into mouse muscle in vivo. Science. 247(4949 Pt 1): 1465-8.
Wool, G.D. et al. (2008) Apolipoprotein A-I mimetic peptide helix No. and helix linker influence potentially anti-atherogenic properties. J Lipid Res. 49(6): 1268-83.
Wool, G.D. et al. (2008) Apolipoprotein A-I mimetic peptide helix number and helix linker influence potentially anti-atherogenic properties. J Lipid Res. 49(6): 1268-83.
Wool, G.D. et al. (2009) An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide. J Lipid Res. 50(9): 1889-900.
Wu, G. et al. (1998) Effect of human apolipoprotein E isoforms on plasma lipids, lipoproteins and apolipoproteins in apolipoprotein E deficient mice. Atherosclerosis. 141:287-96.
Xia et al. (1999) High density lipoproteins (HDL) interrupt the sphingosine kinase signaling pathway. A possible mechanism for protection against atherosclerosis by HDL. J Biol Chem. 274:33143-7.
Yamada, N. et al., Increased Clearance of Plasma Cholesterol After Injection of Apolipoprotein E into Wtanabe Heritable Hyperlipidemic Rabbits. Proc Natl Acad Sci USA. 1989; 86(2):665-9.
Yamamoto et al. (1995) Overexpression of Apolipoprotein E Prevents Development of Diabetic Hyperlipidemia in Transgenic Mice. Diabetes. 44(5):580-5.
Yamamoto et al. (1995) Overexpression of Apolipoprotein E Prevents Development of Diabetic Hyperlipidermia in Transgenic Mice. Diabetes. 44(5):580-5.
Yamashita et al. (2000) Molecular mechanisms, lipoprotein abnormalities and atherogenicity of hyperalphalipoproteinemia. Atherosclerosis. 152:271-85.
Yan et al. (2004) PLTP deficiency improves the anti-inflammatory properties of HDL and reduces the ability of LDL to induce monocyte chemotactic activity. J Lipid Res. 45:1852-8.
Yancey et al. (1995) Efflux of Cellular Cholesterol and Phospholipid to Lipid-free Apolipoproteins and Class A Amphipathic Peptides. Biochemistry. 34:7955-65.
Yip, K.-P. and Marsh, D.J. (1997) An Arg-Gly-Asp peptide stimulates constriction in rat afferent arteriole. Am J Physiol. 273(5 Pt 2): F768-76.
Yla-Herttuala, S. et al. (1991) Macrophages and smooth muscle cells express lipoprotein lipase in human and rabbit atherosclerotic lesions. Proc Natl Acad Sci USA. 88:10143-7.
Yokoyama et al. (1980) The mechanism of activation of lecithin: cholesterol acyltransferase by apolipoprotein A-I and an amphiphilic peptide. J Biol Chem. 255:7333-9.
Yu et al. (2004) Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation. 110:66-73.
Yuan and Altman (1995) Substrate recognition by human RNase P: identification of small, model substrates for the enzyme. EMBO J. 14:159-68.
Yuan et al. (1992) Targeted cleavage of mRNA by human RNase P. Proc Natl Acad Sci USA 89:8006-10.
Yui et al. (1988) Serum prostacyclin stabilizing factor is identical to apolipoprotein A-I (Apo A-I). A novel function of Apo A-1. J Clin Invest. 82: 803-7.
Zabner et al. (1993) Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell. 75:207-16.
Zabner et al. (1994) Safety and efficacy of repetitive adenovirus-mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats. Nat Genet. 6:75-83.
Zaiou et al. (2000) Apolipoprotein E-low density lipoprotein receptor interaction. Influences of basic residue and amphipathic α-helix organization in the ligand. J Lipid Res. 41:1087-95.
Zeiher, A.M. et al. (1994) Coronary Atherosclerotic Wall Thickening and Vascular Reactivity in Humans: Elevated High-Density Lipoprotein Levels Ameliorate Abnormal Vasoconstriction in Early Atherosclerosis. Circulation. 89(6):2525-32.
Zhang et al, "Converting Peptides into Drug Leads by Lipidation," Current Medicinal Chemistry 19:1602-1618 (2012) . *
Zhang, C. et al. (2001) L-arginine chlorination products inhibit endothelial nitric oxide production. J Biol Chem. 276: 27159-65.
Zhang, R. et al (2002) Myeloperoxidase functions as a major enzymatic catalyst for initiation of lipid peroxidation at sites of inflammation. J Biol Chem. 277:46116-22.
Zhang, S.H. et al., Spontaneous Hypercholesterolemia and Arterial Lesions in Mice Lacking Apolipoprotein E. Science. 1992; 258(5081):468-71.
Zhang, W.-J. et al. (2002) Lack of inhibitory effect of HDL on TNF α-induced adhesion molecule expression in human aortic endothelial cells. Atherosclerosis. 165:241-9.
Zhang, Z. et al. (2007) D-4F, An Apolipoprotein A-I Mimetic Peptide, Prevents Endothelial Dysfunction Induced by Myeloperoxidase-Derived Hypochlorous Acid. FASEB J. 21:706-11 (Meeting Abstract).
Zhao et al. (2002) Selective interleukin-12 synthesis defect in 12/15- lipoxygenase deficient macrophages associated with reduced atherosclerosis in a mouse model of familial hypercholesterolemia. J Biol Chem. 277: 35350-6.
Zhu, B. et al. (2000) Apolipoprotein E inhibits neointimal hyperplasia after arterial injury in mice. Am J Pathol. 157:1839-48.
Zhu, Y., and Hui, D.Y. (2003) Apolipoprotein E binding to low density lipoprotein receptor related protein-1 inhibits cell migration via activation of cAMP dependent protein kinase A. J. Biol. Chem. 278:36257-63.
Zilversmit, D.E. (1979) Atherogenesis: a postprandial phenomenon. Circulation. 60:473-85.
Zuker, M. (1989) On finding all suboptimal foldings of an RNA molecule. Science. 244:48-52.

Also Published As

Publication number Publication date
MX383117B (en) 2025-03-13
BR112017001860A2 (en) 2018-02-27
JP2021006529A (en) 2021-01-21
US20170209537A1 (en) 2017-07-27
EP3189069A1 (en) 2017-07-12
AU2015298263B2 (en) 2020-05-14
AU2015298263A1 (en) 2017-03-16
WO2016018665A1 (en) 2016-02-04
US10653747B2 (en) 2020-05-19
JP7081923B2 (en) 2022-06-07
EP3189069A4 (en) 2018-03-07
EP3189069B1 (en) 2024-10-23
CA2954475A1 (en) 2016-02-04
MX2017001432A (en) 2017-05-09
CA2954475C (en) 2023-05-16
IL250302B (en) 2022-07-01
JP2017528437A (en) 2017-09-28
CN107074923B (en) 2021-08-03
JP7095037B2 (en) 2022-07-04
CN107074923A (en) 2017-08-18
IL250302A0 (en) 2017-03-30

Similar Documents

Publication Publication Date Title
US10653747B2 (en) ApoE mimetic peptides and higher potency to clear plasma cholesterol
US8048851B2 (en) Peptides and peptide mimetics to treat pathologies characterized by an inflammatory response
US8617615B2 (en) Charged lipoprotein complexes and their uses
JP4364222B2 (en) Orally administered peptides that improve atherosclerosis
AU2017203911B2 (en) Apolipoprotein mimetics and uses thereof
DE69837809T2 (en) APOLIPOPROTEIN A-I AGONISTS AND THEIR USE FOR THE TREATMENT OF DISLIPIDEMIC ILLNESSES
DE69837855T2 (en) APOLIPOPROTEIN A-I AGONISTS AND THEIR APPLICATION FOR THE TREATMENT OF DYSLIPIDARY DISEASE
US20100227825A1 (en) Peptides and peptide mimetics to treat cancer
KR20010030802A (en) Apolipoprotein A-I Agonists and their use to treat dyslipidemic disorders
US20210324043A1 (en) ApoC-II Mimetic Peptides
S. Getz et al. HDL apolipoprotein-related peptides in the treatment of atherosclerosis and other inflammatory disorders
JP2007534612A (en) Reverse cholesterol transport mediator for the treatment of hypercholesterolemia
HK1242718B (en) Apoe mimetic peptides and higher potency to clear plasma cholesterol
HK1242718A1 (en) Apoe mimetic peptides and higher potency to clear plasma cholesterol
AU2012202223B2 (en) Charged lipoprotein complexes and their uses

Legal Events

Date Code Title Description
FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO UNDISCOUNTED (ORIGINAL EVENT CODE: BIG.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: SMAL); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

AS Assignment

Owner name: ANJI PHARMACEUTICALS INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LIPIMETIX DEVELOPMENT, INC.;REEL/FRAME:060398/0812

Effective date: 20220615

AS Assignment

Owner name: UAB RESEARCH FOUNDATION, ALABAMA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ANANTHARAMAIAH, GATTADAHALLI M.;REEL/FRAME:062456/0868

Effective date: 20170324

AS Assignment

Owner name: LIPIMETIX DEVELOPMENT, LLC, MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:GOLDBERG, DENNIS;REEL/FRAME:062988/0786

Effective date: 20170727

Owner name: LIPIMETIX DEVELOPMENT, INC., MASSACHUSETTS

Free format text: CHANGE OF NAME;ASSIGNOR:LIPIMETIX DEVELOPMENT, LLC;REEL/FRAME:063100/0715

Effective date: 20150623