US20210196789A1 - Heparin-binding domain of igfbp-2 in the treatment of metabolic disorders - Google Patents

Heparin-binding domain of igfbp-2 in the treatment of metabolic disorders Download PDF

Info

Publication number
US20210196789A1
US20210196789A1 US17/057,871 US201917057871A US2021196789A1 US 20210196789 A1 US20210196789 A1 US 20210196789A1 US 201917057871 A US201917057871 A US 201917057871A US 2021196789 A1 US2021196789 A1 US 2021196789A1
Authority
US
United States
Prior art keywords
seq
peptide
hbd1
set forth
glucose
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.)
Abandoned
Application number
US17/057,871
Other languages
English (en)
Inventor
Thomas Delale
Stephane Milano
Thierry Abribat
David Clemmons
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.)
Amolyt Pharma SAS
Original Assignee
Amolyt Pharma SAS
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 Amolyt Pharma SAS filed Critical Amolyt Pharma SAS
Priority to US17/057,871 priority Critical patent/US20210196789A1/en
Assigned to AMOLYT PHARMA reassignment AMOLYT PHARMA ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CLEMMONS, DAVID, MILANO, STEPHANE, ABRIBAT, THIERRY, DELALE, Thomas
Publication of US20210196789A1 publication Critical patent/US20210196789A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • 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
    • C07K14/575—Hormones
    • C07K14/655—Somatostatins
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61K38/1754—Insulin-like growth factor binding proteins
    • 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
    • A61K47/56—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • 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
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4743—Insulin-like growth factor binding protein
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/50—Cyclic peptides containing at least one abnormal peptide link
    • C07K7/52—Cyclic peptides containing at least one abnormal peptide link with only normal peptide links in the ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/64—Cyclic peptides containing only normal peptide links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C07K14/575—Hormones
    • C07K14/65—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2

Definitions

  • the present technology generally relates to compounds, in particular peptides comprising the heparin-binding domain (HBD) of insulin-like growth factor binding protein-2 (IGFBP-2) for the prevention and/or the treatment of metabolic disorders.
  • the present technology also generally relates to uses of such compounds in methods for preventing or treating metabolic disorders and to compositions and formulations for such uses.
  • IGFBP-2 Insulin-like growth factor binding protein-2
  • IGFBP-2 Insulin-like growth factor binding protein-2
  • IGFBP-2 is the second most abundant binding protein in serum. It circulates in concentrations in humans that vary between 100-600 ng/ml in healthy subjects. Protein concentrations are high during fetal life and at birth and fall progressively during childhood and adolescence. There is approximately 25% increase that occurs between 60-80 years of age. Serum concentrations of IGFBP-2 are regulated by hormones and nutrients. Fasting causes a significant increase in IGFBP-2 and feeding (particularly feeding protein) restores concentrations to normal.
  • IGFBP-2 In addition to its role as a carrier protein for Insulin-like growth factors, IGFBP-2 regulates bone mass, fat metabolism and glucose metabolism. IGFBP-2 knockout mice (IGFBP-2 ⁇ / ⁇ ) have reduced bone mass and increased fat mass (DeMambro, Endocrinology, 2008). In contrast, overexpression of IGFBP-2 in mice led to reduced susceptibility to diet-induced obesity and improved insulin sensitivity (Wheatcroft, Diabetes, 2007; Hedbacker, Cell Metab, 2010). In vitro, IGFBP-2 directly stimulates murine and human osteoblast differentiation (Xi, JBMR, 2014) and in contrast inhibits preadipocyte differentiation (Wheatcroft, Diabetes, 2007). As for other IGFBPs, the N-terminal region of IGFBP-2 contains an IGF-I binding site, whereas the C-terminal region facilitates IGF-I binding and accounts for its ability to bind to extracellular matrix.
  • IGFBP-2 also comprises two heparin binding domains (HBD) that confer IGF-binding independent functions.
  • HBD1 is a unique HBD that is located in the linker region whereas HBD2 is located in the C-terminal region. While both HBD1 and HBD2 account for the ability of IGFBP-2 to inhibit adipogenesis (Xi, Endocrinology, 2013), only HBD1 mediates properties on bone mass acquisition and on osteoblast differentiation (Kawai, JBC, 2011; Xi, JBMR, 2014).
  • WO 2005/014635 discloses Cardiovascular disorder Plasma Polypeptides (CPPs) sharing amino acid sequence similarities with HBD1 and suggests a potential diagnostic function for such CPPs.
  • CPPs Cardiovascular disorder Plasma Polypeptides
  • U.S. Pat. No. 9,220,746 discloses HBD1 peptides which conserve the osteoblastogenesis activity of IGFBP-2 and proposes a role for these peptides in the treatment of bone-related conditions.
  • WO 2018/145006 has proposed various fragments of HBD which induce bone formation in vivo.
  • IGFBP-2 insulin-like growth factor-1
  • HBD1 and HBD2 were shown to decrease body weight and fat accumulation in mice, HBD1 and HBD2 were shown to have no effect on glucose tolerance, thereby suggesting an absence of involvement of HBDs on glucose metabolism (Xi, 2013).
  • the present technology relates to a method for modulating a metabolic disorder in a subject, the method comprising: administering to the subject a therapeutically effective amount of a peptide consisting of: i) a heparin binding domain (HBD) as set forth in SEQ ID NO: 1 or an analog thereof; ii) a fragment of the peptide set forth in i); or iii) a pharmaceutically acceptable salt of any one of the peptide as set forth in i) and ii).
  • HBD heparin binding domain
  • the present technology relates to an isolated peptide consisting of: i) a heparin binding domain (HBD) as set forth in SEQ ID NO: 1 or an analog thereof; ii) a fragment of the peptide set forth in i); or iii) a pharmaceutically acceptable salt of any one of the peptide as set forth in i) and ii), for its use in the modulation of a metabolic disorder in a subject having a metabolic disorder.
  • HBD heparin binding domain
  • kits comprising: a) a pharmaceutical composition comprising: a therapeutically effective amount of a peptide consisting of: i) a heparin binding domain (HBD) as set forth in SEQ ID NO: 1 or an analog thereof; ii) a fragment of the peptide set forth in i); or iii) a pharmaceutically acceptable salt of any one of the peptide as set forth in i) and ii); and one or more pharmaceutically acceptable carriers; and b) one or more containers for said pharmaceutical composition; and c) instructions for the use thereof in modulating a metabolic disorder.
  • HBD heparin binding domain
  • the present technology relates to a method for improving glucose control in a subject, the method comprising: administering to the subject a therapeutically effective amount of a peptide consisting of: i) a heparin binding domain (HBD) as set forth in SEQ ID NO: 1 or an analog thereof; ii) a fragment of the peptide set forth in i); or iii) a pharmaceutically acceptable salt of any one of the peptide as set forth in i) and ii).
  • HBD heparin binding domain
  • the present technology relates to an isolated peptide consisting of: i) a heparin binding domain (HBD) as set forth in SEQ ID NO: 1 or an analog thereof; ii) a fragment of the peptide set forth in i); or iii) a pharmaceutically acceptable salt of any one of the peptide as set forth in i) and ii), for its use in improving glucose control in a subject.
  • HBD heparin binding domain
  • the present technology relates to a method for improving insulin sensitivity in a subject, the method comprising: administering to the subject a therapeutically effective amount of a peptide consisting of: i) a heparin binding domain (HBD) as set forth in SEQ ID NO: 1 or an analog thereof; ii) a fragment of the peptide set forth in i); or iii) a pharmaceutically acceptable salt or any one of the peptide as set forth in i) and ii).
  • HBD heparin binding domain
  • the present technology relates to a method for restoring glucose homeostasis in a subject, the method comprising: administering to the subject a therapeutically effective amount of a peptide consisting of: i) a heparin binding domain (HBD) as set forth in SEQ ID NO: 1 or an analog thereof; ii) a fragment of the peptide set forth in i); or iii) a pharmaceutically acceptable salt or any one of the peptide as set forth in i) and ii).
  • the method for restoring glucose homeostasis is achieved independently of insulin and insulin-like growth factor-1 (IGF1).
  • the present technology relates to an isolated peptide consisting of: i) a heparin binding domain (HBD) as set forth in SEQ ID NO: 1 or an analog thereof; ii) a fragment of the peptide set forth in i); or iii) a pharmaceutically acceptable salt of any one of the peptide as set forth in i) and ii), for its use in improving insulin sensitivity in a subject.
  • HBD heparin binding domain
  • FIGS. 2A-2C show graphs indicating that a HBD1 fragment according to one embodiment of the present technology improves glucose intolerance in glucose telemetered ob/ob mice, a mouse model with leptin deficiency leading to insulin resistance.
  • FIG. 2B fasting blood glucose levels (average value within 10 min prior to IPGTT) after 28 days of acylated HBD1 (3-11) fragment treatment.
  • FIGS. 3A-3B show graphs indicating that a HBD1 fragment according to one embodiment of the present technology improves glucose intolerance in glucose telemetered ob/ob mice, a mouse model with leptin deficiency leading to insulin resistance.
  • FIG. 4 shows a graph illustrating increased glucose uptake by fully differentiated 3T3 adipocytes treated with HBD1 fragments according to some embodiments of the present technology.
  • the cells were exposed to the test compounds at a concentration of 3 ⁇ g/ml for 24 hours before testing for [ 3 H]-2-deoxyglucose uptake. All tested HBD1 peptides stimulated increased glucose uptake by the 3T3-LI adipocytes.
  • FIGS. 5A-5C show graphs illustrating both dose-dependent ( FIG. 5A ) and time-dependent ( FIG. 5B ) increases in glucose uptake by fully differentiated C2C12 mouse skeletal muscle myotubes when treated with HBD1 fragments according to some embodiments of the present technology.
  • HBD1 SEQ ID NO: 73 C18:0-HLGLEEPKK
  • 1.5 ⁇ M SEQ ID NO: 73 C18:0-HLGLEEPKK
  • addition of HBD1 peptide SEQ ID NO: 73 (C18:0-HLGLEEPKK) in combination with insulin produced an additive increase in glucose uptake ( FIG. 5C ).
  • FIG. 6 shows a graph illustrating dose-dependent phosphorylation (activation) of the Akt pathway by fully differentiated C2C12 mouse skeletal muscle myotubes when treated with a HBD1 fragment according to an embodiment of the present technology.
  • HBD1 SEQ ID NO: 73 C18:0-HLGLEEPKK.
  • the Akt pathway is utilized by both insulin and IGF1 to ultimately induce GLUT4 translocation to the cell membrane to facilitate the uptake and metabolism of glucose.
  • the activation of Akt by HBD1 peptide SEQ ID NO: 73 was prevented by treatment with anti-fibronectin antibodies, which have been previously demonstrated to prevent binding of IGFBP2 to the RPTP ⁇ receptor and activation of the Akt pathway.
  • FIG. 7 shows a graph illustrating dose-dependent phosphorylation (activation) of the AMPK pathway by fully differentiated C2C12 mouse skeletal muscle myotubes when treated with a HBD1 fragment according to one embodiment of the present technology.
  • HBD1 SEQ ID NO: 73 C18:0-HLGLEEPKK.
  • the AMPK pathway is both insulin and IGF1 independent, but acts ultimately to induce GLUT4 translocation to the cell membrane to facilitate the uptake and metabolism of glucose.
  • HBD1 peptide SEQ ID NO: 73 (C18:0-HLGLEEPKK) was prevented by both treatment with anti-fibronectin antibodies, which have been previously demonstrated to prevent binding of IGFBP2 to the RPTP ⁇ receptor and activation of the Akt pathway, and treatment with the AMPK-specific inhibitor, Compound C (CC).
  • FIG. 8 shows a graph illustrating increased glucose uptake by fully differentiated C2C12 mouse skeletal muscle myotubes when treated with a HBD1 fragment according to one embodiment of the present technology.
  • 1.5 ⁇ M of SEQ ID NO: 73 (C18:0-HLGLEEPKK), both alone and in an additive manner with insulin.
  • the increased uptake of glucose by HBD1 peptide SEQ ID NO: 73 (C18:0-HLGLEEPKK) was prevented by both treatment with anti-fibronectin antibodies, which have been previously demonstrated to prevent binding of IGFBP2 to the RPTP ⁇ receptor, and treatment with the AMPK-specific inhibitor, Compound C (CC).
  • the term “about” is used herein explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/or measurement conditions for such given value.
  • the term “about” in the context of a given value or range refers to a value or range that is within 20%, preferably within 15%, more preferably within 10%, more preferably within 9%, more preferably within 8%, more preferably within 7%, more preferably within 6%, and more preferably within 5% of the given value or range.
  • the present disclosure stems from the work performed by the present discoverers on peptide fragments of IGFBP-2, in particular on peptide fragments of the heparin binding domain (HBD) of IGFBP-2, and on their study of how these peptide fragments can be used in methods of modulating metabolic disorders in a subject, such as in methods of preventing and/or treatment metabolic disorders.
  • the discoverers have found that the peptide fragments of the heparin binding domain 1 (HBD1) of IGFBP-2 can be used to, inter alia, modulate glucose metabolism in a subject by demonstrating that these peptides improve the overall glucose intolerance in animal models resistant to insulin.
  • HBD1 is intended to refer to a peptide having the amino acid sequence as set forth in SEQ ID NO: 1, namely: 1 -KHHLGLEEPKKLR- 13 , wherein “ 1 ” refers to amino acid residue at the 5′-end or at the N-Terminal of this HBD1 peptide and “ 13 ” refers to amino acid residue at the 3′-end or at the C-Terminal of this HBD1 peptide. Accordingly, the amino acids of HBD1 occupy the following positions:
  • amino acids including levorotatory amino acids (L-amino acids or L or L-form) and dextrorotary amino acids (D-amino acids or D or D-form), Alanine (Ala or A), Arginine (Arg or R), Asparagine (Asn or N), Aspartic acid (Asp or D), Cysteine (Cys or C), Glutamic acid (Glu or E), Glutamine (Gln or Q), Glycine (Gly or G), Histidine (His or H), Isoleucine (Ile or I), Leucine (Leu or L), Lysine (Lys or K), Methionine (Met or M), Phenylalanine (Phe or F), Proline (Pro or P), Serine (Ser or S), Threonine (Thr or T), Tryptophan (Trp or W), Tyrosine (Tyr or Y) and Valine (Val or V).
  • L-amino acids or L or L-form and dex
  • L-amino acid residue within the native peptide sequence may be altered to any one of the 20 L-amino acids commonly found in proteins or any one of the corresponding D-amino acids, rare amino acids, such as, but not limited to, 4-hydroxyproline or hydroxylysine, or a non-protein amino acid, such as P-alanine or homoserine. Unless otherwise indicated, an amino acid named herein refers to the L-form.
  • Naturally-occurring variations of the peptides defined herein are those that may comprise substitutions, additions or deletions of one or more amino acids which result due to discrete changes in the nucleotide sequence of the encoding gene or alleles thereof or which result due to alternative splicing of the transcribed RNA. It is understood that these changes do not substantially affect the properties, pharmacological and biological characteristics of the peptide variants.
  • the peptides of the present disclosure may be in the form of salts.
  • Particularly the acidic functions of the molecule may be replaced by a salt derivative thereof such as, but not limited to, a trifluoroacetate salt.
  • peptide By “peptide”, “polypeptide” or “protein” is meant any chain of amino acids, regardless of length or post-translational modification (e.g., glycosylation or phosphorylation), or chemical modification, or those containing unnatural or unusual amino acids such as D-Tyr, ornithine, amino-adipic acid.
  • the peptide of the present disclosure comprises a fragment of HBD1.
  • the peptide is 13 amino acids in length.
  • the peptide is 12 amino acids in length.
  • the peptide is 11 amino acids in length.
  • the peptide is 10 amino acids in length.
  • the peptide is 9 amino acids in length.
  • the peptide is 8 amino acids in length.
  • the peptide is 7 amino acids in length.
  • the peptide is 6 amino acids in length.
  • the peptide is 5 amino acids in length.
  • the peptide is 4 amino acids in length.
  • fragment refers to an amino acid fragment of a peptide such as IGFBP-2 or of the HBD of IGFBP-2 or of the HBD1 of IGFBP-2. Fragments of HBD1 are shorter than 13 amino acid residues. Fragments of HBD1 may therefore be 12, 11, 10, 9, 8, 7, 6, 5 or 4 amino acid residues in length. In some embodiments, the fragment of HBD1 is 12 amino acids in length. In some embodiments, the fragment of HBD1 is 11 amino acids in length. In some embodiments, the fragment of HBD1 is 10 amino acids in length. In some embodiments, the fragment of HBD1 is 9 amino acids in length.
  • the fragment of HBD1 is 8 amino acids in length. In some other embodiments, the fragment of HBD1 is 7 amino acids in length. In some other embodiments, the fragment of HBD1 is 6 amino acids in length. In some other embodiments, the fragment of HBD1 is 5 amino acids in length. In some other embodiments, the fragment of HBD1 is 4 amino acids in length.
  • the present disclosure provides peptides having the amino acid sequences depicted in Table 1.
  • HBD1 (1-13) represents the full-length HBD1.
  • the remaining peptides presented in Table 1 are fragments of HBD1 (1-13), wherein amino acid residues at the N-terminal or at the C-terminal or at both the N-terminal and the C-terminal are absent.
  • the peptides of the present disclosure are “purified”, “isolated” or “substantially pure”.
  • the peptides are “purified”, “isolated” or “substantially pure” when they are separated from the components that naturally accompany them.
  • a compound is substantially pure when it is at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99%, by weight, of the total material in a sample.
  • Techniques for purifying or isolating peptides are commonly known and used in the art and will be known to those of skill in the art.
  • certain peptides according to the present disclosure may also be in cyclized form, such that the N- or C-termini are linked head-to-tail either directly, or through the insertion of a linker moiety, such moiety itself generally comprises one or more amino acid residues as required to join the backbone in such a manner as to avoid altering the three-dimensional structure of the peptide with respect to the non-cyclized form.
  • Such peptide derivatives may have improved stability and bioavailability relative to the non-cyclized peptides.
  • Cyclisation may be accomplished by disulfide bond formation between two side chain functional groups, amide or ester bond formation between one side chain functional group and the backbone ⁇ -amino or carboxyl function, amide or ester bond formation between two side chain functional groups, or amide bond formation between the backbone alpha-amino and carboxyl functions. These cyclisation reactions have been traditionally carried out at high dilution in solution. Cyclisation is commonly accomplished while the peptide is attached to the resin. One of the most common ways of synthesizing cyclic peptides on a solid support is by attaching the side chain of an amino acid to the resin.
  • the C- and N-termini can be selectively deprotected and cyclized on the resin after chain assembly.
  • This strategy is widely used, and is compatible with either tert-butyloxycarbonyl (Boc) or 9-fluorenylmethoxycarbonyl (Fmoc) protocols.
  • Boc tert-butyloxycarbonyl
  • Fmoc 9-fluorenylmethoxycarbonyl
  • a number of approaches may be used to achieve efficient synthesis of cyclic peptides.
  • One procedure for synthesizing cyclic peptides is based on cyclisation with simultaneous cleavage from the resin.
  • the deprotected amino group can react with its anchoring active linkage to produce protected cyclic peptides. In general, a final deprotection step is required to yield the target cyclic peptide.
  • the procedures for synthesizing cyclic peptides are well known in the art.
  • analogs of the peptides defined herein refers to a peptide that has the physiological activity of the parent compound thereof, and that includes one or more (e.g., two, three, four, five or six or more) amino acids different from the amino acid sequence of a naturally occurring parent peptide.
  • Such an analog preferably has at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 07%, at least about 98% or at least about 99% of the physiological activity of the parent peptide.
  • the analogs may be as physiologically active as the parent (i.e., has 100% of the physiological activity of the parent peptide) or may be more than about 100%, more than about 110%, more than about 120%, more than about 130%, more than about 140%, more than about 150%, more than about 160%, more than about 170%, more than about 180%, more than about 190%, more than about 200%, or more than about 300% physiologically active than the parent peptide.
  • the analogs may be less physiologically active than the parent (e.g., 95% of the physiological activity of the parent peptide) but may still present a level of activity that is relevant and/or desirable for some therapeutic applications.
  • Such different amino acids may be additions, substitutions, deletions, or combinations thereof, including addition of non-natural side-chain groups and backbone links
  • Modifications of peptides to produce analogs thereof are known. See, e.g., U.S. Pat. Nos. 7,323,543; 7,482,171; 7,459,152; and 7,393,919, which are all incorporated herein by reference.
  • analogs of peptides comprising HBD1 or analogs of fragments of HBD1 refer to either: i) structural analogs; ii) functional analogs; or iii) structural and functional analogs of HBD1 which are, inter alia, capable of replacing HBD1 in modulating glucose metabolism, such as for example, in preventing and/or treating metabolic disorders associated with impaired glucose metabolism and/or impaired insulin metabolism.
  • Analogs of the peptides of the present disclosure that have at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98% or at least 99% sequence homology with the amino acid sequences described herein over its full length, and sharing at least one of the metabolic effects or biological activity of HBD1.
  • a person skilled in the art would readily identify an analog sequence of HBD1 or an analog sequence of a fragment of HBD1.
  • analogs of HBD1 include, but are not limited to, peptides having the amino acid sequence as forth in SEQ ID NO: 1 (KHHLGLEEPKKLR), wherein the K or the H at position 1, 2 or 3 is substituted with R or K, the L at position 4 or 6 is substituted with I or V, the K at position 10 or 11 is substituted with H or R, the L at position 12 is substituted with I or V and/or the R at position 13 is substituted with K or H.
  • KHHLGLEEPKKLR peptides having the amino acid sequence as forth in SEQ ID NO: 1
  • Analogs of HBD1 or analogs of fragment of HBD1 are, for example, analogs obtained by alanine scans or by amino acid substitutions.
  • analogs of HBD1 or analogs of fragments thereof may comprise a non-naturally encoded amino acid, wherein the non-naturally encoding amino acid refers to an amino acid that is not one of the common amino acids or pyrrolysine or selenocysteine, or an amino acid that occur by modification (e.g. post-translational modification) of naturally encoded amino acid (including, but not limited to, the 20 common amino acids or pyrrolysine and selenocysteine) but are not themselves incorporated into a growing polypeptide chain by the translation complex.
  • non-naturally-occurring amino acids include, but are not limited to, N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine and O-phosphotyrosine.
  • Table 2 presents examples of analogs of HBD1 (3-11) with alanine substitutions at different amino acid positions.
  • Table 3 presents other examples of analogs of HBD1 fragments comprising amino acid substitutions at different amino acid positions of HBD1 (3-11).
  • the analogs of HBD1 or fragments thereof may differ in sequence from HBD1 by 1, 2, 3, 4, 5, 6, 7, 8 or 9 amino acid substitutions, deletions, or additions, or combinations thereof.
  • the amino acid substitution is a conservative amino acid substitution.
  • conservative amino acid substitution refers to substitutions that substitute a residue with another of like characteristics.
  • Typical conservative amino acid substitutions include those among Gly (G), Ala (A), Val (V), Leu (L) and Ile (I); those among Ser (S), Cys (C), Met (M) and Thr (T); those among the acidic residues Asp (D) and Glu (E); those among Asn (N) and Gln (Q); those among the basic residues His (H), Lys (K) and Arg (R); and those among the aromatic residues Phe (F), Try (W) and Tyr (Y).
  • the present technology provides an isolated peptide having a fragment of HBD1 as set forth in SEQ ID NO: 1.
  • the fragment is between 6 to 10 amino acids in length and comprises residues 3 to 10 of HBD1, namely: HLGLEEPK as set forth in SEQ ID NO: 7 or an analog thereof.
  • HLGLEEPK as set forth in SEQ ID NO: 7 or an analog thereof.
  • Examples of analogs of a peptide having the amino acid sequence HLGLEEPK include, but are not limited to the peptides presented in Table 4.
  • the present technology provides an isolated peptide having a fragment of HBD1 as set forth in SEQ ID NO: 1.
  • the fragment is between 6 to 10 amino acids in length and comprises residues 5 to 10 of HBD1, namely: GLEEPK as set forth in SEQ ID NO: 14 or an analog thereof.
  • the fragment is between 6 to 9 amino acids in length and comprises residues 5 to 10 of HBD1, namely: GLEEPK as set forth in SEQ ID NO: 14 or an analog thereof.
  • Examples of analogs of a peptide having the amino acid sequence GLEEPK include, but are not limited to the peptides presented in Table 5.
  • the peptides of the present disclosure may be modified.
  • the term “modified” when used to qualify a peptide refers to any changes made to a peptide, such as changes to the length of the peptide, the amino acid sequence, chemical structure, co-translational modification, or post-translational modification of a peptide.
  • the peptides of the present disclosure comprise one or more amino acid residues that are modified.
  • post-translational modification refers to any modification of a natural or non-natural amino acid that occurs to such an amino acid after it has been incorporated into a peptide chain.
  • the term encompasses, by way of example only, co-translational in vivo modifications, co-translational in vitro modifications (such as in cell-free translation system), post-translational in vivo modifications, and post-translational in vitro modifications.
  • post-translational modifications are, but are not limited to, glycosylation, pegylation, acetylation, acylation, amidation, methylation, carboxylation, phosphorylation, addition of salts, amides or esters, in particular C-terminal esters, and N-acyl derivatives of the peptides of the present disclosure.
  • These types of post-translational modifications are well known in the art.
  • the peptides of the present disclosure include one or more poly(ethylene glycol) (or “PEG”) moiety of between about 10,000 and about 40,000 molecular weight coupled to either the N- or C-terminus of the peptide.
  • PEG poly(ethylene glycol)
  • “PEG” means straight or branched polyalkylene glycol polymers including, but not limited to, polyethylene glycol (PEG), polypropylene glycol (PPG), and polybutylene glycol (PBG), as well as co-polymers of PEG, PPG and PBG in any combination, and includes the monoalkylether of the polyalkylene glycol.
  • the polyalkylene glycol in the peptides of the present disclosure can be, but is not limited to, polyethylene glycol, polypropylene glycol, polybutylene glycol, and any combination thereof.
  • the polyalkylene glycol is polyethylene glycol or “PEG.”
  • PEG subunit refers to a single polyethylene glycol unit, i.e., —(CH 2 CH 2 O)—.
  • the polyalkylene glycol e.g., PEG
  • the polyalkylene glycol can be non-polydispersed, monodispersed, substantially monodispersed, purely monodispersed, or substantially purely monodispersed.
  • “Monodispersed” is used to describe a mixture of compounds wherein about 100 percent of the compounds in the mixture have the same molecular weight.
  • “Substantially monodispersed” is used to describe a mixture of compounds wherein at least about 95 percent of the compounds in the mixture have the same molecular weight.
  • “Purely monodispersed” is used to describe a mixture of compounds wherein about 100 percent of the compounds in the mixture have the same molecular weight and have the same molecular structure.
  • a purely monodispersed mixture is a monodispersed mixture, but a monodispersed mixture is not necessarily a purely monodispersed mixture.
  • “Substantially purely monodispersed” is used to describe a mixture of compounds wherein at least about 95 percent of the compounds in the mixture have the same molecular weight and have the same molecular structure.
  • a substantially purely monodispersed mixture is a substantially monodispersed mixture, but a substantially monodispersed mixture is not necessarily a substantially purely monodispersed mixture.
  • Table 6 presents examples of peptides of the present disclosure that are modified by pegylation.
  • the peptides of the present disclosure include one or more acyl group(s) coupled to any amino acid of the peptide.
  • the one or more acyl group(s) is coupled to the N-terminal or the C-terminal amino acid or to both.
  • acylation of the peptides of the present disclosure is a fatty acylation by which a fatty acid is added to one or more particular amino acid(s) of the peptide.
  • fatty acylation examples include addition of: lauric acid (C12:0), tridecyclic acid (C13:0), myristic acid (C14:0), pentadecyclic acid (C15:0), palmitic acid (C16:0), margaric acid (C17:0), stearic acid (C18:0), nonadecyclic acid (C19:0), arachidinic acid (C20:0), heneicosylic acid (C21:0), behenic acid (C22:0), tricosylic acid (C23:0), or lignoceric acid (C24:0), or a mixture thereof to one or more amino acid of the peptides of the present disclosure.
  • lauric acid C12:0
  • tridecyclic acid C13:0
  • myristic acid C14:0
  • pentadecyclic acid C15:0
  • palmitic acid C16:0
  • margaric acid C17:0
  • stearic acid C18:0
  • the fatty acid to be added may be unsaturated (e.g., monounsaturated or polyunsaturated).
  • unsaturated fatty acids include but are not limited to: i) monounsaturated fatty acid: crotonic acid, myristoleic, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, gadoleic, eicosenoic acid, erucic acid, nervonic acid; ii) di-unsaturated fatty acid: linoleic acid, eicosadienoic acid, docosadienoic acid; iii) tri-unsaturated fatty acids: linolenic acid, pinolenic acid, eleostearic acid, mead acid, dihomo- ⁇ -linolenic acid, eicosatrienoic acid; iv) tetra-unsaturated fatty acid:
  • the peptides of the present disclosure may be coupled to fatty acids that comprise one or more carboxylic functional groups (—COOH).
  • fatty acids that comprise one or more carboxylic functional groups (—COOH).
  • —COOH carboxylic functional groups
  • the peptides of the present disclosure may be coupled to a linker or a linker group (e.g., linker moiety).
  • linker or “linking group” includes non-amino acid linking groups such as are known in the art (see, e.g., U.S. Pat. Nos. 7,468,418; 7,402,652; and 7,351,797, which are all incorporated herein by reference) or variations thereof that will be apparent to those skilled in the art.
  • the peptides of the present disclosure may include more than one modification (e.g., may include a PEG group and an acyl group).
  • the peptides of the present disclosure may be coupled to a modifying group which is itself modified.
  • the peptides of the present disclosure may be coupled to a fatty acid which is itself modified.
  • the modified fatty acid may, for example, be coupled to a linker or a linker group and the linker or the linker group may itself be coupled to another modifying group such as a PEG group or one or more carboxylic functional groups (—COOH).
  • a linker or a linker group such as a PEG group or one or more carboxylic functional groups (—COOH).
  • polynucleotides include isolated polynucleotides which encode the HBD1 peptides, fragments and analogs defined herein.
  • polynucleotide refers to a molecule comprised of a plurality of deoxyribonucleotides or nucleoside subunits.
  • the linkage between the nucleoside subunits can be provided by phosphates, phosphonates, phosphoramidates, phosphorothioates, or the like, or by nonphosphate groups as are known in the art, such as peptoid-type linkages utilized in peptide nucleic acids (PNAs).
  • PNAs peptide nucleic acids
  • the linking groups can be chiral or achiral.
  • the oligonucleotides or polynucleotides can range in length from 2 nucleoside subunits to hundreds or thousands of nucleoside subunits.
  • oligonucleotides are preferably 5 to 100 subunits in length, and more preferably, 5 to 60 subunits in length, the length of polynucleotides can be much greater (e.g., up to 100).
  • the polynucleotide may be any of DNA and RNA.
  • the DNA may be in any form of genomic DNA, a genomic DNA library, cDNA derived from a cell or tissue, and synthetic DNA.
  • the present disclosure may, in certain aspects, use vectors which include bacteriophage, plasmid, cosmid, or phagemid.
  • polypeptides useful in the present technology may be prepared in any suitable manner as known in the art.
  • Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means and methods for preparing such polypeptides are well known in the art.
  • treat As used herein, the terms “treat,” “treating” and “treatment” as used herein all refer to any type of treatment that imparts a benefit to a subject afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the disease, or the like.
  • modulation or the term “modulating” refers to both upregulation (i.e., activation or stimulation) and downregulation (i.e., inhibition or suppression) of a response, or the two in combination or apart.
  • the terms “subjects” or “patient” generally relates a mammalian or non-mammalian animal including, for example and without limitation, a human, a rat, a mouse or farm animal Reference to a subject does not necessarily indicate the presence of a disease or disorder.
  • the term “subject” includes, for example, a mammalian or non-mammalian animal being dosed with a peptide of the present technology as part of an experiment, a mammalian or non-mammalian animal being treated to help alleviate a disease or disorder, and a mammalian or non-mammalian animal being treated prophylactically to retard or prevent the onset of a disease or disorder.
  • Subject mammals may be human subjects of any age, such as an infant, a child, an adult or an elderly adult.
  • the peptides of the present disclosure may be used for controlling, regulating, modulating, preventing, improving, ameliorating, and/or treating metabolic disorders.
  • metabolic disorders refers to, but is not limited to, disorders associated with abnormal or impaired metabolic processes. Examples of metabolic disorders include, but are not limited to, disorders associated with impaired acid-base imbalance, disorders associated with impaired calcium metabolism, disorders associated with impaired glucose metabolism, disorders associated with impaired carbohydrate metabolism, disorders associated with impaired iron metabolism, disorders associated with impaired lipid metabolism, malabsorption syndromes, metabolic syndrome, disorders associated with impaired leptin metabolism, disorders associated with impaired insulin metabolism, and disorders associated with impaired insulin-like growth factor metabolism.
  • the peptides of the present disclosure may be used for modulating glucose metabolism. In some implementations of these embodiments, the peptides of the present technology may be used for modulating glucose metabolism in subjects that are afflicted with a disorder associated with impaired glucose metabolism. In some other implementations of these embodiments, the peptides of the present technology may be used for controlling, regulating, modulating, preventing, improving, ameliorating, and/or treating a disorder associated with impaired glucose metabolism in a subject.
  • disorders associated with impaired glucose metabolism refers to a disorder in which plasma glucose is not maintained within the normal range.
  • disorders associated with impaired glucose metabolism include, but are not limited to: hypoglycemia; hyperglycemia; carbohydrate intolerance; glucose intolerance; impaired fasting glucose; impaired glucose tolerance; carbohydrate-lipid metabolism disturbance; hyperinsulinemia; Type IV hyperlipoproteinemia; insulin resistance; diabetes Type I; diabetes Type II; obesity; impaired beta cell function and acromegaly; rare genetic disorders of obesity such as, but not limited to: disorders associated with impaired melanocortin-4 (MC4) signaling pathway, leptin receptor (LEPR) deficiency, LEPR mutations, leptin receptor-related monogenic obesity, syndrome of extreme insulin resistance; proopiomelanocortin (POMC) deficiency, POMC heterozygous, Alström syndrome, Bardet-Biedl syndrome (BBS), Donohue syndrome (leprechaunism), Rabson-Menden
  • the metabolic disorder is a disorder associated with impaired insulin metabolism.
  • disorder associated with impaired insulin metabolism refers to a disorder associated with one of: synthesis, circulation and degradation of insulin, as well as to disorders associated with impaired pancreatic functions.
  • disorders associated with impaired insulin metabolism include, but are not limited to, metabolic syndrome, dyslipidemia, atherosclerosis, hypertension, obesity, hyperinsulinemia, glucose intolerance, hypertension, peripheral arterial disease, type A syndrome, type B syndrome, endothelial dysfunction, diabetes, microalbuminuria, and impaired fibrinolysis.
  • metabolic syndrome refers to a multiplex risk factor that arises from insulin resistance accompanying abnormal adipose deposition and function. It is comprised of a combination of risk factors for coronary heart disease, as well as for diabetes, fatty liver, and several cancers.
  • Clinical manifestations of metabolic syndrome include the following: hypertension, hyperglycemia, hypertriglyceridemia, reduced high-density lipoprotein cholesterol (HDL-C), abdominal obesity, chest pain or shortness of breath: Suggesting the rise of cardiovascular and other complications, acanthosis nigricans, hirsutism, peripheral neuropathy, retinopathy, xanthomas and xanthelasmas.
  • the peptides of the present disclosure may be used to lower plasma glucose levels in a subject, and/or to improve overall tolerance and/or resistance of a subject to glucose. In some implementations of these embodiments, the peptides of the present disclosure may be used in the management of diabetes in a subject. In some implementations of these embodiments, the peptides of the present disclosure may be used in the prevention of diabetes in a subject. In some implementations of these embodiments, the peptides of the present disclosure may be used in the treatment of diabetes in a subject. In some implementations of these embodiments, the diabetes is Type I diabetes. In some other implementations of these embodiments, the diabetes is Type II diabetes.
  • the peptides of the present disclosure may be used for regulating insulin metabolism.
  • the peptides of the present disclosure may be used to increase insulin secretion, increase insulin sensitivity, decrease insulin resistance, and/or overcome insulin deficiency.
  • the peptides of the present technology may be used for controlling, regulating, modulating, preventing, improving, ameliorating, and/or treating hypoglycemia; hyperglycemia; carbohydrate intolerance; glucose intolerance; impaired fasting glucose; impaired glucose tolerance; carbohydrate-lipid metabolism disturbance; hyperinsulinemia; Type IV hyperlipoproteinemia; insulin resistance; diabetes Type I; diabetes Type II; obesity; impaired beta cell function and acromegaly; rare genetic disorders of obesity such as, but not limited to: disorders associated with impaired melanocortin-4 (MC4) signaling pathway, leptin receptor (LEPR) deficiency, LEPR mutations, leptin receptor-related monogenic obesity, syndrome of extreme insulin resistance; proopiomelanocortin (POMC) deficiency, POMC heterozygous, Alström syndrome, Bardet-Biedl syndrome (BBS), Donohue syndrome (leprechaunism), Rabson-Mendenhall syndrome, syndrome of extreme insulin resistance type A, type BRS
  • the uses and methods defined herein comprise administering to a subject a therapeutically effective amount of a peptide as defined herein to achieve the effects discussed here.
  • therapeutically effective amount refers to the amount of peptides of the present disclosure which is effective for producing some desired therapeutic effect as defined herein at a reasonable benefit/risk ratio applicable to any medical treatment.
  • a dosage is from about 0.01 ⁇ g/kg to about 100 mg/kg, from about 0.01 ⁇ g/kg to about 50 mg/kg, from about 0.01 ⁇ g/kg to about 10 mg/kg, from about 0.01 ⁇ g/kg to about 5 mg/kg, from about 0.1 ⁇ g/kg to about 100 mg/kg, from about 0.1 ⁇ g/kg to about 50 mg/kg, from about 0.1 ⁇ g/kg to about 10 mg/kg, from about 0.1 ⁇ g/kg to about 5 mg/kg, from about 1 ⁇ g/kg to about 100 mg/kg, from about 1 ⁇ g/kg to about 50 mg/kg, from about 1 ⁇ g/kg to about 10 mg/kg, from about 1 ⁇ g/kg to about 5 mg/kg, from about 1 ⁇ g/kg to about 100 mg/kg, from about 1 ⁇ g/kg to about 50 mg/kg, from about 1 ⁇ g/kg to about 10 mg/kg, from about 1 ⁇ g/kg to about 5
  • the dosage is from about 0.001 mg/kg, about 0.05 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg or about 1.0 mg/kg, up to about 30 mg/kg, or about 40 mg/kg.
  • the dosage is about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 31 mg/kg, about 32 mg/kg, about 33 mg/kg, about 34 mg/kg, about 35 mg/kg, about 36 mg/kg, about 37 mg/kg, about 38 mg/kg, about 39 mg/kg, about 40 mg/kg, about 41 mg/kg, about
  • therapeutically effective dosages include: between about 1 and about 50 mg/kg/96 hr; between about 1 and about 50 mg/kg/48 hr; between about 1 and about 50 mg/kg/36 hr; between about 1 and about 50 mg/kg/24 hr; between about 1 and about 50 mg/kg/12 hr; between about 1 and about 25 mg/kg/96 hr; between about 1 and about 25 mg/kg/48 hr; between about 1 and about 25 mg/kg/36 hr; between about 1 and about 25 mg/kg/24 hr; between about 1 and about 25 mg/kg/12 hr; between about 1 and about 10 mg/kg/96 hr; between about 1 and about 10 mg/kg/48 hr; between about 1 and about 10 mg/kg/36 hr; between about 1 and about 10 mg/kg/24 hr; between about 1 and about 10 mg/kg/12 hr; between about 1 and about 5 mg/kg/96 hr; between about 1 and about 5 mg/kg/
  • Concurrently administering or “concurrently administer” as used herein means that the two or more peptides, compounds or compositions are administered closely enough in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occurring within a short time period before or after each other, e.g., sequentially).
  • Simultaneous concurrent administration may be carried out by, for example, mixing the compounds prior to administration, or by administering the compounds at the same point in time but at different anatomic sites and/or by using different routes of administration.
  • active agent refers to a peptide as defined herein.
  • terapéuticaally acceptable refers to a peptide, a compound, or a composition that is suitable for administration to a subject to achieve the effects described herein, such as the treatment defined herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
  • the peptides described above may be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9th Ed. 1995).
  • the peptide (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the composition and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the peptide as a unit-dose formulation, for example, a tablet, which may contain from about 0.01 or about 0.5% to about 95% or about 99% by weight of the peptide.
  • One or more active compounds may be incorporated in the compositions of the present disclosure, which may be prepared by any of the well-known techniques of pharmacy comprising admixing the components, optionally including one or more accessory ingredients.
  • composition of the present disclosure include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical (i.e., both skin and mucosal surfaces, including airway surfaces) and transdermal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular peptide which is being used.
  • buccal e.g., sub-lingual
  • vaginal e.g., parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous)
  • topical i.e., both skin and mucosal surfaces, including airway surfaces
  • transdermal administration i.e., both skin and mucosal surfaces, including airway surfaces
  • compositions suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the peptide; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • Such compositions may be prepared by any suitable method of pharmacy which includes the step of bringing into association the peptide and a suitable carrier (which may contain one or more accessory ingredients as noted above).
  • compositions of the present disclosure are prepared by uniformly and intimately admixing the peptide with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • a tablet may be prepared by compressing or molding a powder or granules containing the peptide, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s).
  • Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
  • compositions suitable for buccal (sub-lingual) administration include lozenges comprising the peptide in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the peptide in an inert base such as gelatin and glycerin or sucrose and acacia.
  • compositions of the present disclosure suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the peptide, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient.
  • Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
  • the composition may be presented in unit ⁇ dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • an injectable, stable, sterile composition comprising a peptide as defined herein, or a salt thereof, in a unit dosage form in a sealed container.
  • the peptide or salt is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject.
  • the unit dosage form typically comprises from about 10 mg to about 10 grams of the peptide or salt.
  • emulsifying agent which is physiologically acceptable may be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier.
  • emulsifying agent is phosphatidyl choline.
  • compositions suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the peptide as defined herein with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
  • compositions suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • compositions suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • Compositions suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the peptide as defined herein.
  • Suitable compositions comprise citrate or bis ⁇ tris buffer (pH 6) or ethanol/water and contain from 0.1M to 0.2M active ingredient.
  • the present disclosure provides liposomal formulations of the peptide disclosed herein and salts thereof.
  • the technology for forming liposomal suspensions is well known in the art.
  • the peptide as defined herein or salt thereof is an aqueous-soluble salt
  • the peptide or salt will be substantially entrained within the hydrophilic center or core of the liposomes.
  • the lipid layer employed may be of any conventional composition and may either contain cholesterol or may be cholesterol-free.
  • the salt may be substantially entrained within the hydrophobic lipid bilayer which forms the structure of the liposome.
  • the liposomes which are produced may be reduced in size, as through the use of standard sonication and homogenization techniques.
  • the liposomal formulations containing the active agents disclosed herein or salts thereof may be lyophilized to produce a lyophilizate which may be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
  • compositions may be prepared from the water-insoluble active agent disclosed herein, or salts thereof, such as aqueous base emulsions.
  • the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the active agent or salt thereof.
  • Particularly useful emulsifying agents include phosphatidyl cholines, and lecithin.
  • the peptides of the present disclosure may be delivered to a subject in need thereof using a medical device, in particular using orthopedic medical devices.
  • medical devices that may be useful for delivering the peptides of the present disclosure include, but are not limited to, sponges (e.g., collagen sponges, gelatin sponges, or the like), dressing, gauges, stents, cages (e.g., intervertebral cages, fusion cages, or the like), bone cement, bone mixers, bone substitutes, pins, anchors, buttons, prostheses, screws (e.g., facet screws, pedicle screw systems, bone screws, or the like), spacers, intramedullary nails, stems (e.g., hip stems or the like), custom implants, plates (e.g., humerous plates, wrist plates, radius plates, cervical plates, lumbar plates or the like), and trauma products.
  • the peptides of the present disclosure may be incorporated into the materials used to make
  • the peptides of the present disclosure may be delivered to a subject in need thereof using a delivery device such as a particle (e.g., nanoparticles or microparticles) or an encapsulation system (e.g., microcapsules, microspheres).
  • a delivery device such as a particle (e.g., nanoparticles or microparticles) or an encapsulation system (e.g., microcapsules, microspheres).
  • the peptides of the present disclosure may be dispersed throughout the materials forming the delivery systems, such as for example, polymeric chains, or may be located into pores or cavities formed into the delivery system.
  • the release of the peptides from such delivery systems may be controlled (i.e., slow release, sustained release or controlled release). Examples of particles and particles and encapsulation systems that may be used to deliver the peptides of the present disclosure are well known in the art.
  • the pharmaceutical compositions may contain other additives, such as pH-adjusting additives.
  • useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate.
  • the compositions may contain microbial preservatives.
  • Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use.
  • kits comprising one or more peptides as defined herein together with instructions for use of kit according to the applications defined herein.
  • Example 1 HBD1 Peptide Improves Glucose Tolerance In Vivo
  • HBD1 peptide reduced the plasma glucose levels in response to the IP glucose tolerance test, thereby suggesting a role for HBD1 peptides in glycemic control.
  • HBD1 peptides for the treatment of clinical conditions associated with glucose intolerance or insulin resistance, such as, but not limited to, type 2 diabetes, leptin deficiency, leptin receptor deficiency, and extreme insulin resistance syndromes.
  • HBD1 peptides were assessed in glucose-telemetered obese ob/ob mice after twice daily administration of HBD peptides for 28 consecutive days.
  • IPGTT intraperitoneal glucose tolerance test
  • HBD peptide fragment of SEQ ID NO: 73 (C18:0-HLGLEEPKK) was administered twice daily at 8-hour ⁇ 1 hour interval between the two daily administrations.
  • the first day of dosing was designated as Day 1.
  • Bolus injection was carried out using a sterile syringe and the needle was introduced subcutaneously, 2 to 4 injection sites were used in rotation.
  • the hair of the animals on the injection area was clipped prior to the first injection and then as necessary during the treatment period.
  • the volume administered was 5 mL/kg/administration. Individual dose volumes were calculated using the latest body weight. On day 27, 16-hour mean blood glucose levels were assessed in normal fed conditions. On day 28, fasted (4 hours) mice were injected intraperitoneally with glucose at 1 g/kg. Plasma blood glucose profile (expressed as mg/dL) was recorded every minute up to 3-hour post glucose injection.
  • Intraperitoneal glucose tolerance test (IPGTT)—On the morning of the IGPTT day (day 28), 2-hour fasted animals were treated with vehicle or with the HBD fragment.
  • Glucose solution was administered 2 hours ⁇ 15 minutes post-dosing (vehicle or a peptide as set forth in SEQ ID NO: 73 (C18:0-HLGLEEPKK). Blood glucose was monitored from 10 minutes before (fasting condition) to 3-hour post-glucose challenge. Food was re-introduced 4 hours post-glucose challenge. The second treatment of the day (the HBD fragment or vehicle) was performed 2 hours after food re-introduction.
  • FIG. 2 shows that, after 4 weeks of administration, the test peptide decreased fasting glucose levels and glucose excursion following IPGTT. A marked effect was observed at the dose of 3 mg/kg.
  • FIGS. 3A-3B also show a positive effect on glucose control, as the test peptide was able to markedly decrease 16-hour average blood glucose levels in these mice exhibiting severe hyperglycemia at baseline.
  • 3T3-LI cells are a mouse fibroblast cell line which when cultured under specific conditions, differentiate into adipocytes.
  • 3T3-L1 cells were seeded in 24-well plates and cultured in 3T3-L1 maintenance medium (DMEM containing 10% fetal bovine serum, 4 mM L-glutamine 1 mM, sodium pyruvate) until the cells were 100% confluent. The cells were then fed with 3T3-L1 maintenance medium and cultured for a further 48 h.
  • 3T3-L1 maintenance medium DMEM containing 10% fetal bovine serum, 4 mM L-glutamine 1 mM, sodium pyruvate
  • the medium was changed to Differentiation medium 1 (DMEM containing 10% fetal bovine serum, 4 mM L-glutamine, 1 mM sodium pyruvate, 0.5 mM IBMX, 0.25 mM dexamethasone 1 mg/ml insulin), and cultured for a further 2 days.
  • Differentiation medium 2 DMEM containing 10% fetal bovine serum, 4 mM L-glutamine, 1 mM sodium pyruvate, 1 mg/ml insulin
  • Adipocyte Maintenance medium (DMEM containing 10% fetal bovine serum, 4 mM L-glutamine, 1 mM sodium pyruvate), and cultured for a further 7 days. During this time, the medium was changed every other day.
  • DMEM Adipocyte Maintenance medium
  • Stock solutions of the HBD1 peptides to be tested were prepared by dilution with 0.9% NaCl solution under sterile conditions in a laminar flow cabinet to a concentration of 1 mg/ml, based on net peptide content. The solutions were homogenized by gentle inversion. Test items were prepared from the stock solutions, and remaining stock solution was aliquoted and stored at ⁇ 20° C. and used without repeated freeze-thaw cycles.
  • Glucose uptake experiments were carried our using the following protocol. Prior to beginning the experiment, 100 ml of Krebs Ringer bicarbonate buffer (KRBB)(25 mM Hepes pH 7.4, 118 mM NaCl, 5 mM NaHCO 3 , 4.7 mM KCl, 1.2 mM KH2PO 4 , 1.2 mM MgSO 4 , 2.5 mM CaCl 2 , 0.2% BSA—Filtered using a 0.2 ⁇ m filter) and 100 ml of Incubation medium (DMEM containing 4 mM L-glutamine, 1 mM sodium pyruvate, 1% penicillin streptomycin, 0.2% BSA—Filtered using a 0.2 ⁇ m filter) were pre-warmed to 37° C., and 500 ml of KRBB was chilled on ice.
  • KRBB Krebs Ringer bicarbonate buffer
  • test compounds were diluted to 3 ⁇ g/ml final concentrations in pre-warmed Incubation medium and in pre-warmed KRBB.
  • Insulin positive control
  • Insulin previously diluted 1:1000 in sterile 0.9% NaCl, was further diluted in 10 ml of both medium and buffer to a final concentration of 1 nM. All traces of the medium were carefully removed from the cells using a fine tip.
  • 1 ml of incubation medium containing study compounds or vehicle was added to the appropriate wells. No insulin was added at this time. The plate was incubated at 37° for 24 h.
  • HBD1 peptides SEQ ID NO: 1 (KHHLGLEEPKKLR), SEQ ID NO: 10 (HLGLEEPKK), SEQ ID NO: 16 (HHLGLEEPKK), and SEQ ID NO: 73 (C18:0-HLGLEEPKK), were tested in the described assay to determine the effect on glucose uptake by the 3T3-LI adipocytes.
  • Results of HBD1 peptide incubation on glucose uptake by the differentiated 3T3-LI adiopocytes are presented in FIG. 4 .
  • all tested HBD1 peptides stimulated increased glucose uptake by the 3T3-LI adipocytes.
  • IGFBP2 insulin-like growth factor 2
  • RPTP ⁇ Receptor-Type Protein Tyrosine Phosphatase- ⁇
  • the medium was changed to differentiation medium (DMEM with 25 mM glucose and 2% horse serum) for 6 days with medium changed every third day.
  • the various treatments were diluted in serum-free medium and, after washing the cells with serum-free medium, were added to the cells and incubated for 2 hours or alternative times, depending on the treatment.
  • the media was removed and 1.0 ml of glucose-free Krebs ringer bicarbonate buffer (pH 7.4), containing the same treatments, was added and incubation continued for 10 minutes.
  • the wells were then rinsed three times with ice cold phosphate buffered saline, the cells were extracted with 0.5 N NaOH, and the 3 H-2-deoxyglucose content of the cell lysate quantitated by scintillation counting.
  • the cells were prepared the same way except 6-well plates were used. After 6 days incubation in differentiating medium, the cells were washed with serum-free medium. The various treatments were then added in serum free medium containing 0.1% BSA. HBD1 peptides were added and incubated for 8 hours. When utilizing IGF-I, incubation was for 15 minutes after IGF-1 addition. Following incubation the cells were lysed in RIPA buffer and sonicated. The cell lysate was centrifuged and the supernatant analyzed for either Akt or AMPK by SDS PAGE using a 10% gel followed by immunoblotting with the appropriate antibody.
  • HBD1 peptide SEQ ID NO: 73 When tested for ability to increase glucose uptake by fully differentiated C2C12 mouse skeletal muscle myotubes, HBD1 peptide SEQ ID NO: 73 (C18:0-HLGLEEPKK), stimulated increased glucose uptake as compared with vehicle-treated controls in both a dose- and time-dependent manner ( FIGS. 5A-5B ). Further, addition of HBD1 peptide SEQ ID NO: 73 (C18:0-HLGLEEPKK) in combination with insulin produced an additive increase in glucose uptake ( FIG. 5C ).
  • HBD1 peptide SEQ ID NO: 73 C18:0-HLGLEEPKK
  • cell lysate proteins were separated by SDS PAGE and immunoblotted with anti-Akt pS473 antibodies. It was observed that HBD1 peptide SEQ ID NO: 73 (C18:0-HLGLEEPKK) induced a dose-related increase in phosphorylated Akt ( FIG. 6 ).
  • FN3 anti-fibronectin antibodies
  • HBD1 peptide SEQ ID NO: 73 C18:0-HLGLEEPKK
  • cell lysate proteins were separated by SDS PAGE and immunoblotted with anti-pAMPK T172. It was observed that treatment with HBD1 peptide SEQ ID NO: 73 (C18:0-HLGLEEPKK) resulted in a dose-dependent increase in phosphorylated AMPK ( FIG. 7 ).
  • phosphorylated AMPK was completely abolished by treatment with either anti-fibronectin antibodies (FN3), which have been demonstrated to prevent interaction with the RPTP ⁇ receptor, and which have previously been demonstrated to block IGFBP2 interaction with RPTP ⁇ (Shen et al. 2012), or with Compound C, a specific inhibitor of AMPK activation, and which has also previously been demonstrated to block IGFBP2-stimulated glucose uptake in cultured adipocytes (Assefa et al. 2017).
  • FN3 anti-fibronectin antibodies
  • Compound C a specific inhibitor of AMPK activation
  • HBD1, HBD1 fragments and analogs thereof in modulating glucose metabolism, insulin metabolism as well as leptin metabolism.
  • the mechanism of action of HBD1 on osteoblast differentiation and on glucose uptake is similar, in that they share the same receptor (RPTPbeta) and the same intracellular pathways (Akt). Therefore it can be envisioned that the HBD1 analogs that have shown potency in osteoblast differentiation (as per osteoblast differentiation assays previously reported in, for example, WO 2018/145006) will also be effective on glucose metabolism.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • General Chemical & Material Sciences (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Toxicology (AREA)
  • Emergency Medicine (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Immunology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
US17/057,871 2018-05-24 2019-05-23 Heparin-binding domain of igfbp-2 in the treatment of metabolic disorders Abandoned US20210196789A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/057,871 US20210196789A1 (en) 2018-05-24 2019-05-23 Heparin-binding domain of igfbp-2 in the treatment of metabolic disorders

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201862676087P 2018-05-24 2018-05-24
US17/057,871 US20210196789A1 (en) 2018-05-24 2019-05-23 Heparin-binding domain of igfbp-2 in the treatment of metabolic disorders
PCT/IB2019/054302 WO2019224786A1 (en) 2018-05-24 2019-05-23 Heparin-binding domain of igfbp-2 in the treatment of metabolic disorders

Publications (1)

Publication Number Publication Date
US20210196789A1 true US20210196789A1 (en) 2021-07-01

Family

ID=68615210

Family Applications (2)

Application Number Title Priority Date Filing Date
US16/420,656 Active US11192932B2 (en) 2018-05-24 2019-05-23 Heparin-binding domain of IGFBP-2 in the treatment of metabolic disorders
US17/057,871 Abandoned US20210196789A1 (en) 2018-05-24 2019-05-23 Heparin-binding domain of igfbp-2 in the treatment of metabolic disorders

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US16/420,656 Active US11192932B2 (en) 2018-05-24 2019-05-23 Heparin-binding domain of IGFBP-2 in the treatment of metabolic disorders

Country Status (6)

Country Link
US (2) US11192932B2 (de)
EP (1) EP3801591A4 (de)
JP (1) JP2021525261A (de)
CN (1) CN112566653A (de)
CA (1) CA3100665A1 (de)
WO (1) WO2019224786A1 (de)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2018214650B2 (en) 2017-02-06 2022-04-14 Amolyt Pharma Compounds, compositions and uses thereof for improvement of bone disorders

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19757250A1 (de) * 1997-12-22 1999-07-01 Forssmann Wolf Georg Prof Dr Insulin-like growth factor binding protein und seine Verwendung
EP1198565A1 (de) 1999-07-07 2002-04-24 Maxygen Aps Verfahren zur herstellung von modifizierten polypeptiden
AUPR030900A0 (en) 2000-09-22 2000-10-12 Queensland University Of Technology Growth factor complex
US7049286B2 (en) * 2001-08-30 2006-05-23 Diatos, S.A. Insulin conjugates and methods of use thereof
JP2008500952A (ja) 2003-07-15 2008-01-17 ジェノバ・リミテッド 心臓血管障害で減少する分泌ポリペプチド種
AU2006228989B2 (en) 2005-03-30 2012-06-14 Murdoch Childrens Research Institute Methods and agents for modulating cellular activity
EP2462946B1 (de) 2006-08-16 2014-07-09 National Research Council of Canada Methode zur Inhibierung der Cathepsin Aktivität
CA2704397C (en) 2007-11-01 2018-01-23 Mayo Foundation For Medical Education And Research Hla-dr binding peptides and their uses
WO2010096125A1 (en) * 2008-10-29 2010-08-26 The Rockefeller University Methods and kits for treating disease by administering insulin-like growth factor binding protein-2
WO2010141811A2 (en) 2009-06-04 2010-12-09 The University Of North Carolina At Chapel Hill Compounds and methods for treating bone disorders and controlling weight
GB2503148A (en) * 2011-02-24 2013-12-18 Vermillion Inc Biomarker panels diagnostic methods and test kits for ovarian cancer
JP6382111B2 (ja) * 2012-03-01 2018-08-29 ノヴォ ノルディスク アー／エス Ｎ末端改変オリゴペプチド及びその使用
KR101482708B1 (ko) * 2012-10-09 2015-01-14 성균관대학교산학협력단 헤파린 결합 도메인을 포함하는 ｉｇｆｂｐ-5의 ｃ-말단 도메인의 신생 혈관 생성 억제제로서의 신규한 용도
JP2016513645A (ja) * 2013-03-12 2016-05-16 ザ・ユニヴァーシティ・オヴ・ノース・キャロライナ・アト・チャペル・ヒル 肥満の処置および体重の制御のための化合物および方法
AU2018214650B2 (en) 2017-02-06 2022-04-14 Amolyt Pharma Compounds, compositions and uses thereof for improvement of bone disorders

Also Published As

Publication number Publication date
JP2021525261A (ja) 2021-09-24
EP3801591A1 (de) 2021-04-14
US11192932B2 (en) 2021-12-07
US20190359676A1 (en) 2019-11-28
CA3100665A1 (en) 2019-11-28
EP3801591A4 (de) 2022-03-09
WO2019224786A1 (en) 2019-11-28
CN112566653A (zh) 2021-03-26

Similar Documents

Publication Publication Date Title
JP6143740B2 (ja) 持続性ペプチド類似体
JP4855268B2 (ja) アルツハイマー治療剤
US11725037B2 (en) Peptide dual agonists of GIPR and GLP2R
JPH0768138B2 (ja) インシュリン様成長因子及び類似体を用いる障害治療方法
WO2006058539A2 (en) Growth hormone secretagogue receptor 1a ligands
EP2937088B1 (de) Zusammensetzung mit gewebereparaturwirkung und verwendung davon
KR20120082909A (ko) 합성 마이오스타틴 펩티드 길항제
KR20160118264A (ko) 스테로이드제 투여로 유발되는 성장 장해에 대한 의약
KR20200024263A (ko) 고혈당증의 치료 및 예방을 위한 펩타이드
US8673852B2 (en) Methods of treating neuronal disorders using MNTF peptides and analogs thereof
CN103764669A (zh) 抗炎药物产品
CN114423447A (zh) 用于延释组合物的疏水性肽盐
US11192932B2 (en) Heparin-binding domain of IGFBP-2 in the treatment of metabolic disorders
US10947285B2 (en) Compounds, compositions and uses thereof for improvement of bone disorders
KR20180135016A (ko) 페길화 생활성 펩타이드 및 그의 용도
CN109475604A (zh) 长效型clr/ramp激动剂的配量和用途
KR20080021588A (ko) 메카노 성장 인자 펩티드 및 이들의 용도
AU2003262552A1 (en) Use of human growth hormone in multiple system atrophy
JP4760377B2 (ja) ＧＰＲ１０３−ｌｉｋｅ受容体蛋白質に対するリガンドの新規用途
ZA200600646B (en) Use of human growth hormone in multiple system atrophy

Legal Events

Date Code Title Description
AS Assignment

Owner name: AMOLYT PHARMA, FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DELALE, THOMAS;MILANO, STEPHANE;ABRIBAT, THIERRY;AND OTHERS;SIGNING DATES FROM 20210202 TO 20210208;REEL/FRAME:055552/0668

STPP Information on status: patent application and granting procedure in general

Free format text: APPLICATION DISPATCHED FROM PREEXAM, NOT YET DOCKETED

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION