WO2017120350A1 - Constructions peptidiques combinées à des médicaments à base de statine et utilisation de celles-ci - Google Patents

Constructions peptidiques combinées à des médicaments à base de statine et utilisation de celles-ci Download PDF

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WO2017120350A1
WO2017120350A1 PCT/US2017/012353 US2017012353W WO2017120350A1 WO 2017120350 A1 WO2017120350 A1 WO 2017120350A1 US 2017012353 W US2017012353 W US 2017012353W WO 2017120350 A1 WO2017120350 A1 WO 2017120350A1
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vpgy
simvastatin
statin
cancer
peptide
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PCT/US2017/012353
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S. Kenny ROBERTS
Samir M. Parikh
Chandra C. GHOSH
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Roberts S Kenny
Parikh Samir M
Ghosh Chandra C
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1021—Tetrapeptides with the first amino acid being acidic

Definitions

  • This invention relates to libraries of isolated aggregating peptides, peptide mimetics and repeat units that are formulated with inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase commonly known as statins to improve efficacy and or toxicity profile compared to naked drug.
  • Tie2 is an endothelial-enriched receptor tyrosine kinase whose activation by Angiopoietin-1 (Angpt-1) prevents vascular leakage against a broad spectrum of microbial and inflammatory mediators (12-14). Infections and systemic inflammation induce secretion and de novo synthesis in the vasculature of another Tie2 ligand called Angpt-2 that acts as a context-specific Tie2 antagonist (15-18).
  • Angpt-1 Angiopoietin-1
  • statins In human sepsis, falciparum malaria, polytrauma, and related critical illnesses, circulating Tie2 ligands tilt heavily toward Angpt-2— shown in >30 studies spanning >4000 subjects (12). Genetic deletion or targeted Angpt-2 inhibition confers protection against vascular leak, lung injury, and death in models of sepsis and ARDS (7, 19, 20). In applying an unbiased drug screen, statins have emerged as potent inhibitors of vascular Angpt-2 production (21). Given orally to treat hypercholesterolemia, statins undergo extensive first-pass hepatic metabolism, resulting in poor bioavailability with a peak plasma concentration in 1-2 hours post administration.
  • statins applied to endothelial cells exert an on-target suppressive effect on Angpt-2 at nanomolar concentrations. Further, statins have been linked to FOXOl (also known as FKHR - forkhead in
  • rhabdomyosarcoma belongs to the forkhead box O-class (FoxO) subfamily of the forkhead transcription factors. Mounting evidence suggests that the human FOXOl protein, a founding member of the FoxO family is likely involved in carcinogenesis, diabetes and other human diseases. (Huarui Lu and Haojie Huang; FOXOl: A potential target for human diseases, Curr Drug Targets. 2011 Aug; 12(9): 1235-1244.
  • the Angpt/Tie2 system consists of the endothelial-enriched receptor tyrosine kinase called Tie2 and its major circulating ligands, Angpt-1 and Angpt-2 (Fig 1) (24).
  • Angpt-1 produced by peri-endothelial cells continually activates Tie2.
  • Angpt-2 is strikingly induced in the endothelium, displacing Angpt-1, and thus inhibiting otherwise tonic Tie2 signaling.
  • Peptide-based nanoparticles devices are one interesting class of material that can be chemically synthesize in high yields and have been shown to form nanostructures, including nanoparticles capable of delivering small molecules, peptides, protein, and siRNA. These constructs can not only be used as passive drug carriers and excipients and in 2D and 3D cell culture systems, but also have potential to target and bind directly to cells as well as being incorporated into the extracellular matrix.
  • peptide-based delivery systems are distinguished by unique efficiencies in accessing stable particles, drug loading, and targeting.
  • human derived peptides that circulate in blood might not be immunogenic. Longer peptides increase immunogenicity, but also increase the chance for cross-reactivity. In contrast, short peptide sequences avoid complex tertiary structure that can increase immunogenicity short peptide-based drug carriers attractive.
  • peptide fragments that are inspired by tropoelastin fragments, we designed several formulations of peptide(s), peptide mimetics and repeat units, comprising various combinations of certain amino acids that can be combined with statins for administering to patients in need thereof.
  • a library of biocompatible and degradable self -assembling peptides were synthesized and screened for stable formulations of monodiperse nanoparticles. Selected peptides were found to entrap or encapsulate simvastatin and are active in human microvascular ECs treated cells. These same peptide constructs can be used to manipulate the pharmacological profile of simvastatin based on the ability to tune key features of peptide aggregates or nanostructures including size, surface charge, stability, drug loading and release kinetics. The peptides described herein can therefore be used as formulation vehicle for various hydrophobic and hydrophilic drugs including the simvastatin and rapamycin.
  • the instant application relates to a peptide-statin based formulations that demonstrate activity in mice subjected to either of two distinct models of sepsis.
  • the peptide-statin construct comprises one or more peptide of the form VPGI or VPGY and a statin, or a
  • the present application provides a composition comprising an aggregated peptide construct comprising a peptide having any ofhte amino acid sequences described in any of the embodiments supra and a statin drug, or a pharmaceutically acceptable salt thereof.
  • the aggregated peptide construct comprises one or more peptides of the form VPGI or VPGY and simvastatin, or a pharmaceutically acceptable salt thereof.
  • the present application provides a composition comprising an aggregated peptide construct comprising a peptide having the amino acid sequence VPGI or VPGY and a statin drug, or a pharmaceutically acceptable salt thereof.
  • the statin drug is selected from the group consisting of lovastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin, atorvastatin, pitivastatin, cerivastatin, and fluvastatin, or a pharmaceutically acceptable salt thereof.
  • the statin drug is lovastatin.
  • the statin drug is fluvastatin.
  • the statin drug is lovastatin.
  • the statin drug is pravastatin.
  • the statin drug is simvastatin.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the carrier is adapted for parenteral administration.
  • the aggregated protein construct is a mixture of a peptide having the amino acid sequence VPGY, a peptide having the amino acid sequence VPGI, and simvastatin.
  • the aggregated protein construct is a 1 : 1 : 1 mixture of a peptide having the amino acid sequence VPGY, a peptide having the amino acid sequence VPGI, and simvastatin.
  • the present application provides a method of treating a mammal for sepsis comprising administrering to the mammal any of the compositions or aggregated peptide constructs described herein, which comprises a therapeutically effective amount of the statin drug, or a pharmaceutically acceptable salt thereof.
  • the present application provides any of the aggregated peptide constructs described herein, comprising a therapeutically effective amount of the statin drug for use in treating sepsis.
  • the present application provides use of any of the aggregated peptide constructs described herein, comprising a
  • statin drug for use in preparation of a medicament for use in treatment of sepsis.
  • the present application provides a method of treating a FOXOl related disease in a mammal in need thereof, comprising administering to the mammal any of the compositions or aggregated peptide constructs described herein, which comprises a therapeutically effective amount of the statin drug, or pharmaceutically acceptable salt thereof.
  • the FOXOl related disease is selected from cancer, diabetes, obesity, muscle atrophy, insulin sensitivity, insulin resistance, impaired glucose tolerance, and an age-related disease.
  • the cancer is a solid tumor.
  • the cancer is prostate cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, melanoma, bone cancer (including osteosarcoma), prostate cancer, colorectal cancer, colon cancer, hepatocellular carcinoma, liver cancer, lung cancer (including non-small cell lung cancer), lymphoma or leukemia.
  • the diabetes is type 2 diabetes.
  • Figure 1 show Angpt-2 induction inhibits Tie2 to potentiate vascular leakage.
  • Figure 2 shows Statins inhibit de novo Angpt-2 production, (clockwise from upper left), i.
  • Statins inhibit HMG-CoA reductase (heptagon), blocking translocation of Foxol (blue oval) into the nucleus, thereby inhibiting Angpt-2 transcription in endothelium, ii.
  • Parental simvastatin improves survival in CLP, but only when lung Angpt-2 expression is intact (siAngpt-2 reduces lung Angpt-2).
  • Parenteral simvastatin lowers lung Angpt-2 during LPS.
  • Figure 3 show Screening simvastatin-peptide formulations.
  • VPGY:VPGI:simvastatin formulation (K series) loaded with 10 mM simvastatin.
  • Figure 4 shows schematic representation of in vivo evaluation of simvastatin nanoparticles in distinct models of sepsis.
  • FIG. 5 shows VPGY:VPGI:simvastatin (Kl) formulation lowers 24 h Sepsis Score following LPS. Kl was compared to empty carrier (NT) and unencapsulated simvastatin injected at an equal dose of 400 mg/kg x 1.
  • FIG. 6 shows Tie2 heterozygous mice suffer more leakage and death in sepsis.
  • Tie2 heterozygotes (+/-) were compared to wildtype (+/+) littermate controls in the LPS and CLP model. (left to right) i. Lung stained with intravenously injected albumin-binding blue dye, indicative of extravasation from vascular leakage, ii. Survival following single LPS injection or (iii) CLP.
  • FIG. 7 shows . Simvastatin reduces angiopoietin-2 (Angpt-2) transcription and binding of the transcription factor Foxol.
  • Angpt-2 mRNA concentrations were measured via real-time polymerase chain reaction (RT-PCR) 24 hr after applying simvastatin (SIM) at indicated
  • HUVECs human umbilical vein endothelial cells
  • B SIM (10 ⁇ ) was applied for 24 hr to HUVECs pretreated with control or Kriippel-like factor-2 (KLF2) siRNA and Angpt-2 mRNA was measured by RT-PCR.
  • C Putative Foxol binding sites were identified at -2,840 and - 1,660 in the three kilobases 5' to the translational start site of human ANGPT2 by TFsearch and crosschecked by aligning the consensus Foxol binding sequence (in bold).
  • HUVECs treated with SIM (10 ⁇ ) for 24 hr were gently lysed and chromatin immunoprecipitation was performed with anti-Foxol.
  • Results of RT-PCR to quantify ANGPT2 promoter concentration are shown for the -2,840 and -1,660 sites. *p ⁇ 0.05, ***p ⁇ 0.001 (see Crit Care Med. 2015;43(7):e230-40).
  • Figure 8 shows Simvastatin prevents nuclear Foxol translocation by phosphorylation.
  • A Endothelial cells (ECs) treated with simvastatin (SIM, 10 ⁇ ) were stained for Foxol (red) and nuclei (4',6-diamidino-2-phenylindole, blue). White arrows indicate the edge of nuclear staining.
  • B Planimetric quantification of staining results by surveying 10 high-powered fields (A ⁇ 40) per slide. *p ⁇ 0.05 and **p ⁇ 0.01.
  • C HUVEC lysates 24 hr after SIM treatment (10 ⁇ ) were immunoblotted with anti-pSer256 Foxol (pFoxo-1), anti-Foxol (tFoxo-1), and anti-GAPDH as a loading control.
  • D Densitometric quantification of the above results.
  • E Immunoblotting as described above for lysates of ECs infected with a virus encoding wild-type Foxol (AdFoxol) for 24 hr and treated with SIM (10 ⁇ ) for 24 hr or vehicle.
  • F Quantification of the above results.
  • Figure 9 shows that Foxol phosphorylation is critical for the suppression of Angpt-2 by simvastatin.
  • A Real-time polymerase chain reaction for Angpt-2 24 hr after treating virally transduced human umbilical vein endothelial cells with simvastatin (SIM, 10 ⁇ ) or vehicle.
  • Gal is a control virus expressing ⁇ -galactosidase
  • AdFoxol is a virus encoding wild-type Foxol
  • Ad-TM-Foxol is a virus encoding the triple phosphorylation constitutively active mutant Foxol.
  • B ELISA for secreted Angpt-2 protein for the above conditions. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001, and ****p ⁇ 0.0001 (see Crit Care Med. 2015;43(7):e230-40).
  • one aspect of the invention provides a statin and peptide(s) or statin and aggregated peptides construct comprised of chemically linked amino acid residues of the following sequence (X1-X2-X3-X4) wherein Xi is isoleucine (He) or a conservative substitution thereof; X2 is proline (Pro) or a conservative substitution thereof; X3 is glycine (Gly) or a conservative substitution thereof; X4 is tyrosine (Tyr) or a conservative substitution thereof that encapsulate or entrap a statin, such as simvastatin.
  • Xi is isoleucine (He) or a conservative substitution thereof
  • X2 is proline (Pro) or a conservative substitution thereof
  • X3 is glycine (Gly) or a conservative substitution thereof
  • X4 is tyrosine (Tyr) or a conservative substitution thereof that encapsulate or entrap a statin, such as simvastatin.
  • one embodiment of this invention includes a statin and peptide(s) or statin and aggregated peptides construct comprising chemically linked amino acid residues of the following sequence: Xi - X 2 - X3 - X4; where Xi is an L- or D-amino acid; X2 is proline, or a conservative substitution thereof; X3 is selected from a group consisting of glycine or a conservative substitution thereof, a bond, and a non-coded, non-proteinogenic, or a non-standard amino acid linker; X 4 is an L- or D-amino acid that encapsulate or entrap simvastatin.
  • statin and peptide(s) or construct where said biological entity is selected from a group consisting of an amine, amide, imine, imide, azide, azo compound, carboxylic acid, carbonate, carboxylate, ester, alcohol, aldehyde, alkane, alkene, alkyne, halogens, ketone, acyl halide, boronic acid, boronic ester, borinic acid, borinic ester, hydroperoxide, peroxide, ether, hemiacetal, hemiketal, acetal, ketal, orthoester, cyanates, nitrate, nitrile, nitrite, nitro compound, nitroso compound, pyridine, thiol, sulfide, disulfide, sulfoxide, sulfone, sulfinic acid, sulfonic acid, thiocyanate, thione, thial, pho
  • the following sequence (X1-X2-X3-X4) is repeated sequentially or randomly to form polypeptides of the following length: 11, 13, 17, 19, 22, 23, 26, 28, 29, 31, 33, 34, 36, 37, 38, 39, 41, 43, 44, 46, 47, 51, 52, 53, 57, 58, 59.
  • the statin and peptide(s) comprises a chemically linked amino acid residue having the sequence Xi - X 2 - X3 - X4.
  • the aggregated peptide construct comprises a chemically linked amino acid residue having the sequence Xi - X 2 - X3 - X4.
  • the aggregated peptide construct consists of a chemically linked amino acid residue has the sequence H- Xi - X 2 - X3 - X4- OH.
  • H is part of the amino group of the amino acid residue
  • OH is part of the carboxyl group of the amino acid residue.
  • the aggregated peptide construct consists of a chemically linked amino acid residue has the sequence HO— Xi— X 2 — X 3 — X 4 — H.
  • the aggregated peptide construct comprises a chemically linked amino acid residue having the sequence Xi - X 2 - X 3 - X4; the aggregated peptide construct consisting of a chemically linked amino acid residue having the sequence Xi - X 2 - X 3 - X4; the aggregated peptide construct consisting of a chemically linked amino acid residue having the sequence H-Xi - X 2 - X 3 - X 4 - OH; or the aggregated peptide construct consisting of a chemically linked amino acid residue having the sequence HO- Xi - X 2 - X 3 - X4-H: Xi is isoleucine (He), glutamic acid (Glu), tyrosine (Tyr), valine (Val), or lysine (Lys).
  • Xi is isoleucine (He). In some embodiments, Xi is glutamic acid (Glu). In some embodiments, Xi is tyrosine (Tyr). In some embodiments, Xi is valine (Val). In some embodiments, Xi is lysine (Lys). In some embodiments, Xi is isoleucine or a conservative substitution thereof. In some embodiments, X 2 is proline. In some embodiments, X3 is glycine. In some embodiments, X4 is isoleucine (He), tyrosine (Tyr), histidine (His), or phenylalanine (Phe).
  • X4 is isoleucine (He). In some embodiments, X4 is tyrosine (Tyr). In some embodiments, X4 is histidine (His). In some embodiments, X4 is phenylalanine (Phe). In some embodiments, Xi is isoleucine (He), glutamic acid (Glu), tyrosine (Tyr), valine (Val), or lysine (Lys); X 2 is proline; X3 is glycine; and X4 is isoleucine (He), tyrosine (Tyr), histidine (His), or phenylalanine (Phe).
  • Xi is isoleucine (He), X 2 is proline, X3 is glycine, and X4 is isoleucine (He).
  • Xi is glutamic acid (Glu)
  • X 2 is proline
  • X3 is glycine
  • X4 is isoleucine (He).
  • Xi is tyrosine (Tyr)
  • X 2 is proline
  • X3 is glycine
  • X4 is isoleucine (He).
  • Xi is valine (Val)
  • X 2 is proline
  • X3 is glycine
  • X4 is isoleucine (He).
  • Xi is lysine (Lys), X 2 is proline, X3 is glycine, and X4 is isoleucine (He). In some embodiments, Xi is isoleucine (He), X 2 is proline, X3 is glycine, and X4 is tyrosine (Tyr). In some embodiments, Xi is glutamic acid (Glu), X 2 is proline, X3 is glycine, and X4 is tyrosine (Tyr). In some embodiments, Xi is tyrosine (Tyr), X 2 is proline, X3 is glycine, and X4 is tyrosine (Tyr).
  • Xi is valine (Val), X 2 is proline, X3 is glycine, and X4 is tyrosine (Tyr).
  • Xi is lysine (Lys)
  • X 2 is proline
  • X3 is glycine
  • X4 is tyrosine (Tyr).
  • Xi is isoleucine
  • Xi is glutamic acid (Glu)
  • X2 is proline
  • X3 is glycine
  • X4 is histidine
  • Xi is tyrosine (Tyr)
  • X 2 is proline
  • X3 is glycine
  • X4 is histidine (His).
  • Xi is valine (Val)
  • X2 is proline
  • X3 is glycine
  • X4 is histidine (His).
  • Xi is lysine (Lys), X2 is proline, X3 is glycine, and X4 is histidine (His).
  • Xi is isoleucine (He)
  • X2 is proline
  • X3 is glycine
  • X4 is phenylalanine (Phe).
  • Xi is glutamic acid (Glu)
  • X2 is proline
  • X3 is glycine
  • X4 is phenylalanine (Phe).
  • Xi is tyrosine (Tyr)
  • X2 is proline
  • X3 is glycine
  • X4 is phenylalanine (Phe).
  • Xi is valine (Val)
  • X2 is proline
  • X3 is glycine
  • X4 is phenylalanine (Phe).
  • Xi is lysine (Lys)
  • X2 is proline
  • X3 is glycine
  • X4 is phenylalanine (Phe).
  • the aggregated peptide construct is terminated with an 8-15 amino acid sequence, wherein the amino acids are selected from cysteine (C), glycine (Gly), histidine (His), arginine (Arg), serine (Ser), and phenylalanine (Phe).
  • the 8-15 amino acid sequence comprises a sequence -Cys-His-His-His-Arg-His-Ser-Phe.
  • the aggregated peptide construct is selected from:
  • the aggregated peptide construct is selected from:
  • the aggregated peptide construct is selected from:
  • n is 2.
  • the aggregated peptide construct is selected from:
  • Another embodiment of this invention includes the aggregated peptide construct, where the amino acid sequence is selected from the group consisting of:
  • VPGY-VPGY-VPK VPGY-VPGY-VPK
  • VPGY-VPGF-VPGY-V VPGY-VPGF-VPGY-V
  • VPGY-VPGY-VPGY-VPGY-VP VPGY-VPGY-VPGY-VPGY-VPG;
  • the invention provides an aggregated peptide construct, wherein the construct is a mixture of peptides, wherein the mixture is selected from:
  • VPGY VPGY-GS-CHHHRHSF.
  • the application provides any of the previous embodiments of aggregated peptide constructs and a statin. In some embodiments, the application provides any of the previous embodiments of aggregated peptide constructs and a statin selected from simvastatin, pravastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, and mevastatin, or a pharmaceutically acceptable salt thereof.
  • statin and peptide(s) formulations wherein the amino acid sequence of the peptide is selected from the group consisting of:
  • IPGY STATIN
  • LPGY STATIN
  • VPGY STATIN
  • EPGY STATIN
  • KPGY STATIN
  • KPGI STATIN
  • TPGY STATIN
  • TPGI STATIN
  • VPGI STATIN
  • VPGW STATIN
  • IPGW STATIN
  • LPGW STATIN
  • IPGY- VPGY- VPG STATIN
  • VPGI-VPGI- VPG STATIN
  • TPGY-TPGY-TPG STATIN
  • IPGY-IPGY-IPG STATIN
  • VPGY-VPGY-VPK STATIN
  • IPGY-IPGY-IPK STATIN
  • VPGY-VPGY-VPH STATIN
  • IPGY-IPGY-IPH STATIN
  • VPGY- VPGF-VPGY- V STATIN
  • VPGY-VPGY-VPGY- V STATIN
  • VPGY- VPGY-VPGY-L STATIN
  • VPGY-VPGY-VPGY- VPGY-V STATIN
  • VPGY-VPGY-VPGY- VPGY-VPG STATIN
  • VPGY-VPGY-VPGY- VPGY-VPGY-VP STATIN;
  • VPGY-VPGY-VPGY- VPGY-VPGY-VPG STATIN;
  • VPGY-VPGY-VPGY-VPGY-VPGY-VP STATIN;
  • VPGY-VPGY-VPGY-VPGY-VPGY-VPGY-VPGY-VPGY-VP STATIN;
  • statin is selected from simvastatin, pravastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, and mevastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is pravastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the STATIN in this embodiment is lovastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the STATIN in this embodiment is atorvastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the STATIN in this embodiment is fluvastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the
  • STATIN in this embodiment is cerivastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is rosuvastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is pitavastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is mevastatin, or a pharmaceutically acceptable salt thereof.
  • the invention provides an aggregated peptide construct, wherein the construct is a mixture of peptides and statin, wherein the mixture is selected from:
  • STATIN is a statin is selected from simvastatin, pravastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, and mevastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is pravastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is lovastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is atorvastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is fluvastatin, or a pharmaceutically acceptable salt thereof.
  • the STATIN in this embodiment is cerivastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the STATIN in this embodiment is rosuvastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the STATIN in this embodiment is pitavastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, the STATIN in this embodiment is mevastatin, or a pharmaceutically acceptable salt thereof.
  • statin and peptide(s) formulations where the amino acid sequence of the peptide is selected from the group consisting of:
  • IPGY SIMVASTATIN
  • VPGY SIMVASTATIN
  • KPGY SIMVASTATIN
  • KPGI SIMVASTATIN
  • TPGY SIMVASTATIN
  • TPGI SIMVASTATIN
  • VPGI SIMVASTATIN
  • VPGW SIMVASTATIN
  • IPGW SIMVASTATIN
  • LPGW SIMVASTATIN
  • IPGY- VPGY- VPG SIMVASTATIN
  • VPGI-VPGI- VPG SIMVASTATIN
  • TPGY-TPGY-TPG SIMVASTATIN
  • IPGY-IPGY-IPG SIMVASTATIN
  • VPGY- VPGY-VPK SIMVASTATIN
  • IPGY-IPGY-IPK SIMVASTATIN
  • VPGY- VPGY-VPH SIMVASTATIN
  • IPGY-IPGY-IPH SIMVASTATIN
  • VPGY- VPGF-VPGY-V SIMVASTATIN
  • VPGY- VPGY-VPGY- V SIMVASTATIN
  • VPGY- VPGY-VPGY-L SIMVASTATIN
  • VPGY-VPGY-VPGY- VPGY-V SIMVASTATIN
  • VPGY-VPGY-VPGY- VPGY-VPGY-VP SIMVASTATIN
  • VPGY-VPGY-VPGY- VPGY-VPGY-VPG SIMVASTATIN
  • VPGY-VPGY-VPGY-VPGY-VP SIMVASTATIN
  • VPGY-VPGY-VPGY-VPGY- VPGY-VPGY-VPGY- VPGY- VP SIMVASTATIN.
  • the invention provides an aggregated peptide construct, wherein the construct is a mixture of peptides and statin, wherein the mixture is selected from:
  • EPGY VPGI: SIMVASTATIN
  • TPGY VPGI: SIMVASTATIN
  • VPGY VPGYG: SIMVASTATIN
  • VPGY VPGI : VPGYHHHRHSF : SIMVASTATIN
  • the construct forms nanoparticles or microparticles. In some embodiments, the construct forms nanoparticles. In some embodiments, the construct forms microparticles.
  • the construct allows for targeted delivery in said patient.
  • the composition further comprises an additional therapeutic or targeting agent.
  • the composition is suitable for intravenous or subcutaneous, administration to a patient.
  • Another embodiment includes a method of increasing the half -life of a drug during administration to a patient, comprising administering to said patient a composition as described herein.
  • Another embodiment includes a method of administering a drug to a patient, comprising administering to said patient a composition as described herein.
  • the aggregated peptide construct is self -assembling.
  • the instant application provides a method of delivering a statin in a patient in need thereof, comprising administering to said patient any of the aggregated peptide constructs described herein, wherein said construct comprises one or more of any of the aggregated peptide constructs disclosed herein, and wherein said construct further comprises a statin drug, or a pharmaceutically acceptable salt thereof.
  • the construct forms nanoparticles or microparticles.
  • the construct allows for targeted delivery in said patient.
  • the statin drug, or a pharmaceutically acceptable salt thereof is encapsulated by the construct.
  • the statin, or a pharmaceutically acceptable salt thereof is encapsulated by the construct, and the statin is not covalently bound to the peptide. In some embodiments, the statin, or a pharmaceutically acceptable salt thereof, is encapsulated by the construct, and the statin is covalently bound to the peptide, optionally via a linker. In some embodiments, the statin, or a pharmaceutically acceptable salt thereof, is non-covalently or affinity bound to a receptor carrier. In some embodiments, the statin, or a pharmaceutically acceptable salt thereof, is modified by a targeting ligand. In some embodiments, the targeting ligand is selected from the group consisting of an antibody, a peptide, and a protein.
  • the statin, or a pharmaceutically acceptable salt thereof is modified by a molecule to increase therapeutic window and blood circulation in said patient.
  • the statin, or a pharmaceutically acceptable salt thereof is modified by a molecule selected from the group consisting of an antibody, PEG, and PLGA.
  • the statin is selected from the group consisting of simvastatin, pravastatin, lovastatin, atorvastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin, and mevastatin, or a pharmaceutically acceptable salt thereof.
  • the statin is simvastatin, or a pharmaceutically acceptable salt thereof.
  • the patient suffers from a disease amenable to treatment by said statin, or a pharmaceutically acceptable salt thereof.
  • the disease is selected from the group consisting of atherosclerosis, cardiovascular disease, a lipid metabolism disorder,
  • ARDS acute respiratory distress syndrome
  • the disease is sepsis.
  • the disease is acute respiratory distress syndrome (ARDS).
  • pharmaceutically acceptable salts refers to derivatives of the disclosed statin drugs, wherein the drug moiety is modified by converting an existing acid or base moiety to its salt form.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of
  • the term "treating" or “treatment” refers to one or more of (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease; (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • preventing the disease for example, preventing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of
  • the phrase "therapeutically effective amount” refers to the amount of active statin drug that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.
  • the dosage of the compound, or a pharmaceutically acceptable salt thereof, administered to a patient or individual is about 1 mg to about 2 g, about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg to about 100 mg, about 1 mg to 50 mg, or about 50 mg to about 500 mg.
  • the term "individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • the aggregated peptide constructs described herein can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, for example, by a continuous perfusion pump.
  • compositions which contain, as the active ingredient, the compound of the invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers (excipients).
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Example 1 Design of exemplary aggregating peptide constructs comprising 4-11 amino acids
  • tropoelastin monomer secreted by elastogenic cells such as smooth muscle cells, endothelial cells, and fibroblasts can aggregate into organized spheres that ultimately gets incorporated into growing elastin fibers.
  • elastogenic cells such as smooth muscle cells, endothelial cells, and fibroblasts
  • a library of highly scalable short linear peptides or their cyclic counterpart was designed that will aggregate in aqueous medium to form micro- and nano- aggregates (micro- and nano- particles) for use in drug delivery, tissue engineering and as formulation vehicle for various therapeutic agents that is both hydrophobic and hydrophilic drugs including the simvastatin and rapamycin.
  • These peptides were shown to entrap simvastatin and can be formulated as homogeneous (one group of unique aggregating peptide sequence) or heterogeneous (two or more groups of unique aggregating peptide sequences) mixtures.
  • statins small molecule drugs
  • DNA DNA
  • siRNA mRNA
  • excipients stabilizers
  • protein drugs for reducing drug toxicity, improving pharmacokinetics (PK), enhancing drug efficacy, targeting agents selectively to disease sites, delivering drugs to intracellular targets, and any combinations thereof.
  • PK pharmacokinetics
  • a diverse library of aggregating peptides and simvastatin e.g., 4-11, amino acids total in length that can be combined with statins, Table 1-3, was designed.
  • the aggregating peptides simvastatin construct can be formulated in aqueous media to generate a series of micro- and nano- structures (e.g., microparticles and nanoparticles) with a capability to control the size of the aggregates from nanometer to micrometer.
  • These aggregating peptides can entrap statins, rapamycin and other therapeutic drugs for nanotherapeutics and nanomedicine, diagnostics, drug delivery, and tissue engineering applications.
  • a candidate peptide sequence such as VPGI, TPGY and so on can be synthesized as described herein, e.g., by solid-state peptide synthesis.
  • the aggregating peptides sequences can also be produced as fusion peptides such as VPGICHHHRHSF,
  • VPGYCHHHRHSF or protein by recombinant gene expression in bacteria e.g. Escherichia coli
  • mammalian cell lines such as the Chinese hamster ovary (CHO), HEK and COS cell lines or any methods known in the art used to produce protein.
  • the aggregating peptide or fusion peptide construct can then be combined with therapeutic drugs such as simvastatin (e.g. VPGY:simvastatin,
  • VPGY:VPGI:simvastatin or rapamycin (e.g. VPGY: rapamycin, VPGY:VPGI: rapamycin) and other small molecules.
  • rapamycin e.g. VPGY: rapamycin, VPGY:VPGI: rapamycin
  • Various aqueous solution including pure water or buffers are added to evaluate stability and drug entrapment. Characterization of any peptide aggregate, including peptide and statin nano or nanostructures formed, e.g., size, shape, stability can be performed using any methods known in the art or as described in the Examples below.
  • Exemplary aggregating peptide comprising linear sequences (4 -11 amino acid sequence) in three- and one- letter codes are shown in Tables 1-5. Each indicated amino acid sequence is designated with a number or letter to which is referred throughout the specification.
  • the short aggregating peptide sequences having the general formula:
  • Xi is an L- or D-amino acid
  • X2, Xe, and X10 is proline, or a conservative substitution thereof
  • X3, X7, and X11 is selected from a group consisting of glycine or a conservative substitution thereof, a bond, and a non-coded, non-proteinogenic, or a non-standard amino acid linker
  • X 4 , Xs, and X12 is an L- or D-amino acid
  • said peptide is terminated with chemical group, molecule, peptide blocking group, peptide, or biological entity.
  • the 4 - 11 amino acids constructs reported here were designed to test the ability to control aggregation properties and stability (Tables 1-3).
  • each peptide in the Tables 1-3 was prepared, for example, by FMOC -based solid-phase peptide synthesis and all of the peptide sequences were verified for >70% purity before by HPLC. The ability of these short hydrophobic peptide sequences to self-organize in aqueous media was then evaluated. As described in detail in the following Examples, the short peptides (as shown in Tables 1-3) formed a particulate suspension spontaneously within seconds in aqueous media and size of aggregate measured by Dynamic light scattering (DLS). These aggregating peptides can be mixed in various combinations and ratios (Table 3-5) in the presence of statin or other therapeutic agent to form particulate suspension of well-defined sized as measured by DLS.
  • DLS Dynamic light scattering
  • Each of the aggregating peptide in Tables 1-5 was prepared by FMOC solid-phase peptide synthesis and can be combined with simvastatin or rapamycin for delivery.
  • these peptides were synthesized on the acid sensitive Wang resin and cleaved from the resin with a solution mixture of trifluoroacetic acid/triisopropylsilane/water in a volume ratio of 9.5/2.5/2.5.
  • Synthesized peptides were purified by reversed phase HPLC or flash column chromatography. The peptide sequences were purified by HPLC using a C18 5 ⁇ 120A 4.6 * 150mm column in 0.1% TFA/H20 (buffer A) and 0.09% TFA in 80% ACN/20 % H20 (buffer B).
  • each of the peptides in Tables 1-5 are combined with a statin. In some embodiments, each of the peptides in Tables 1-5 are combined with a statin selected from lovastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin, atorvastatin, pitivastatin, cerivastatin, and fluvastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, each of the peptides in Tables 1-5 are combined with simvastatin, or a pharmaceutically acceptable salt thereof. In some embodiments.
  • each of the peptides in Tables 1-5 are combined with pravastatin, or a pharmaceutically acceptable salt thereof. In some embodiments. In some embodiments, each of the peptides in Tables 1-5 are combined with lovastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, each of the peptides in Tables 1-5 are combined with atorvastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, each of the peptides in Tables 1-5 are combined with fluvastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, each of the peptides in Tables 1-5 are combined with cerivastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, each of the peptides in Tables 1-5 are combined with rosuvastatin, or a
  • each of the peptides in Tables 1-5 are combined with pitavastatin, or a pharmaceutically acceptable salt thereof. In some embodiments, each of the peptides in Tables 1-5 are combined with mevastatin, or a pharmaceutically acceptable salt thereof.
  • Tables 6-8 shows aggregating amino acid sequences (4 -11 amino acid sequences) in three- and one-letter codes and simvastatin. Each indicated amino acid sequence is designated with an entry number or letter to which is referred throughout the specification.
  • Table 9 shows one-letter code of aggregating fusion sequence (for example peptide carrier fused to peptide drug) with G, GS and GGS linker. Each indicated amino acid sequence is designated with an entry number or letter to which is referred throughout the specification.
  • Table 10 shows one-letter code of combination of isolated aggregating peptide sequence combining different sequences. Each indicated amino acid sequence is designated with an entry number or letter to which is referred throughout the specification.
  • Example 2 Angpt-2 induction inhibits Tie2 to potentiate vascular leakage.
  • the Angpt/Tie2 system consists of the endothelial-enriched receptor tyrosine kinase called Tie2 and its major circulating ligands, Angpt-1 and Angpt-2.
  • Tie2 the endothelial-enriched receptor tyrosine kinase
  • Angpt-1 the major circulating ligands
  • Angpt-1 is produced by peri- endothelial cells and platelets.
  • Angpt-1 is highly matrix-bound and continually activates Tie2.
  • Angpt-2 induced in the endothelium through a least two mechanisms: (1) release of pre-formed protein stored in Weibel-Palade bodies and (2) de novo production via transcription of the ANGPT2 gene.
  • Angpt-2 competes for Tie2 binding with Angpt-1, but antagonizes Tie2 in the endothelium. When Angpt-2 is induced, it therefore displaces Angpt-1 and inhibits otherwise tonic Tie2 signaling. Described below are formulations comprised of statin and peptide that demonstrates efficacy in sepsis models.
  • Statins inhibit de novo Angpt-2 production, (clockwise from upper left), i. Statins inhibit HMG-CoA reductase (heptagon), blocking translocation of Foxol (blue oval) into the nucleus and binding of Foxol to the ANGPT2 promoter, thereby inhibiting its transcription in endothelium. Statins promote phosphorylation of Foxol at key serine and threonine residues (Thr-24, Ser-256, and Ser-319) in a manner dependent on PI3-kinase. ii. Dose-response in ECs for simvastatin. Endothelial cells in culture produce and secrete Angpt-2 protein tonically.
  • simvastatin reduces Angpt-2 protein as detected in the conditioned media of cultured endothelial cells.
  • the IC50 fifty percent inhibitory concentration
  • IC50 fifty percent inhibitory concentration
  • Parental simvastatin 200 mg/kg intraperitoneal doses injected -24 hrs, Ohr, and +12 hrs relative to induction of sepsis improves survival in sepsis as induced by cecal ligation and perforation (CLP), but only when lung Angpt-2 expression is intact (siAngpt-2 reduces lung Angpt-2).
  • CLP cecal ligation and perforation
  • Example 4 Screening simvastatin-peptide formulation. Human microvascular ECs treated with vehicle (NT), 10 ⁇ or 20 ⁇ naked simvastatin (10, 20), or a series of unique
  • VPGY:VPGI:simvastatin formulation (K series) loaded with 10 ⁇ simvastatin, (inset) Cellular uptake of dye-loaded VPGY nanoparticles. Peptides and simvastatin were formulated (1 : 1 or 1 : 1 : 1) for a final concentration of 5 mg/mL in 150mM NaCl.
  • Each unique aggregating peptide constructs or simvastatin were dissolved in DMSO or ethanol (but not limited to these organic solvents- Isopropyl alcohol, ethanol, acetone, dioxane, acetonitrile, methanol, and THF) in separate vials at 50 - 800 mg/ml for peptides and 0.5 to 40 mg/mL for simvastatin.
  • a fix volumes of each was combined then injected or mixed with an aqueous solution that can be water, acid, neutral or alkaline buffer solution (e.g., but not limited to, 150 mM NaCl, Sodium Citrate, Acetate, Phosphate) while stirring or mixing thus allowing for monodisperse particles of varying size and stability.
  • the peptide concentration of the resulting mixture or suspensions are about 5 mg/mL to about 50 mg/mL (weight/volume, w/v).
  • Nano and Micro aggregation can also be induced by adding a precipitation while stirring at about 100 rpm to about 500 rpm for about 1-20 mins. The stirring speed can be varied to control size homogeneity.
  • Dynamic light scattering (DLS) analysis of these constructs confirmed nanostructures formation.
  • Example 6 VPGY:VPGI:simvastatin (Kl) formulation lowers 24 h Sepsis Score following LPS (Ol l l :B4 serotype injected intraperitoneally at 10 mg/kg). Kl was compared to empty carrier (NT) and unencapsulated simvastatin injected at an equal dose of 400 mg/kg intraperitoneal. The Sepsis Score is computed by a battery of physical observations (including core temperature, spontaneous physical activity, fur appearance, and ocular chemosis) conducted by an operator blinded to treatment group.
  • Example 7. Tie2 heterozygous mice suffer more leakage and death in sepsis.
  • Parikh SM Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS.
  • Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies. Blood. 2004;103(11):4150-6.
  • Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol. 2009;29(8):2011-22. PMCID: 2663314.

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Abstract

La présente invention concerne des compositions comprenant des constructions peptidiques formant des agrégats isolés qui sont formulées avec des inhibiteurs de la 3-hydroxy-3-méthylglutaryl-coenzyme A réductase, communément appelés statines ainsi que des méthodes de traitement d'une septicémie, de maladies associées à FOXO1, et d'autres troubles, pour améliorer l'efficacité et le profil de toxicité par comparaison à un médicament nu.
PCT/US2017/012353 2016-01-05 2017-01-05 Constructions peptidiques combinées à des médicaments à base de statine et utilisation de celles-ci WO2017120350A1 (fr)

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EP1714648A1 (fr) * 2004-02-09 2006-10-25 ASKA Pharmaceutical Co., Ltd. Medicament de combinaison
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WO2000048626A2 (fr) * 1999-02-17 2000-08-24 University Of Washington Compositions aerosol d'inhibiteurs de hmg-coa reductase permettant d'inhiber l'inflammation associee a une maladie pulmonaire
EP1714648A1 (fr) * 2004-02-09 2006-10-25 ASKA Pharmaceutical Co., Ltd. Medicament de combinaison
WO2012097054A1 (fr) * 2011-01-11 2012-07-19 Mount Sinai School Of Medicine Méthodes et compositions pour le traitement du cancer et méthodes associées
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