US20230057847A1 - Glp2 receptor agonists and methods of use - Google Patents

Glp2 receptor agonists and methods of use Download PDF

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US20230057847A1
US20230057847A1 US17/782,560 US202017782560A US2023057847A1 US 20230057847 A1 US20230057847 A1 US 20230057847A1 US 202017782560 A US202017782560 A US 202017782560A US 2023057847 A1 US2023057847 A1 US 2023057847A1
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peptide
alkylene
seq
peptide conjugate
amino acid
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Weijun Shen
Peter G. Schultz
Zaid AMSO
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Scripps Research Institute
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    • 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
    • A61K47/54—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 compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • peptide conjugate comprising:
  • the staple is of Formula (I):
  • composition comprising a peptide conjugate described herein and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method for treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a peptide conjugate described herein.
  • A is optionally substituted alkylene. In some embodiments, A is —(CH 2 ) t —, wherein t is 1-12. In some embodiments, A is optionally substituted arylene. In some embodiments, A is —NR 3 -alkylene-NR 3 —. In some embodiments, A is —N—.
  • X 1 and X 2 are —C( ⁇ O)—. In some embodiments, X 1 and X 2 are -alkylene-C( ⁇ O)—. In some embodiments, X 1 and X 2 are —CH 2 —C( ⁇ O)—. In some embodiments, X 1 and X 2 are independently -alkylene-C( ⁇ O)NR 3 —. In some embodiments, X 1 and X 2 are independently —CH 2 —C( ⁇ O)NR 3 —. In some embodiments, X 1 and X 2 are independently -alkylene-C( ⁇ O)NR 3 -alkylene-. In some embodiments, X 1 and X 2 are independently —CH 2 —C( ⁇ O)NR 3 —CH 2 CH 2 —.
  • >A-R has the following structure:
  • >A-R has the following structure:
  • >A-R has the following structure:
  • >A-R has the following structure:
  • >A-R has the following structure:
  • s is 1-15. In some embodiments, s is 1-10. In some embodiments, s is 5-15. In some embodiments, s is 5-10.
  • Y is hydrogen or —CO 2 H.
  • each L is independently —(CR 1 R 2 ) v —, -alkylene-O—, —C( ⁇ O)—, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; and v is 2-20.
  • Y 1 and Y 2 are halogen. In some embodiments, Y 1 and Y 2 are —COOH. In some embodiments, Y 1 and Y 2 are the —S— of two sulfhydryl-containing amino acids in a peptide that modulates the GLP-2 receptor.
  • Y 1 and Y 2 are the —S— of two sulfhydryl-containing amino acids in a peptide
  • Y 1 and Y 2 are —CONH— wherein the —NH— is part of two amine-containing amino acids in a peptide that modulates the GLP-2 receptor.
  • Y 1 and Y 2 CONH— wherein the —NH— is part of two amine-containing amino acids in a peptide that modulates the GLP-2 receptor which are 7 amino acids apart.
  • FIG. 1 A depicts a concentration-response curve of teduglutide and the long-acting GLP2R agonists to the human GLP2R with no serum added.
  • FIG. 1 B depicts a concentration-response curve of teduglutide and the long-acting GLP2R agonists to the human GLP2R with serum added.
  • FIG. 2 depicts a concentration-response curve of teduglutide, the long-acting GLP2R agonists, and apraglutide to the mouse GLP2R.
  • FIG. 3 depicts a concentration-response curve of teduglutide and the long-acting GLP2R agonists to the cyno monkey GLP2R.
  • FIG. 4 A depicts a concentration-response curve of teduglutide and the long-acting GLP2R agonists to GLP1R.
  • FIG. 4 B depicts a concentration-response curve of teduglutide and the long-acting GLP2R agonists to GCGR.
  • FIG. 4 C depicts a concentration-response curve of teduglutide and the long-acting GLP2R agonists to GIPR.
  • FIG. 5 A depicts the thermal stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at 4° C.
  • FIG. 5 B depicts the thermal stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at 25° C.
  • FIG. 5 C depicts the thermal stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at 37° C.
  • FIG. 5 D depicts the thermal stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at 70° C.
  • FIG. 6 A depicts the stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at a pH of 3.3 and a temperature of 4° C.
  • FIG. 6 B depicts the stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at a pH of 3.3 at room temperature.
  • FIG. 6 C depicts the stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at a pH of 37.5 and a temperature of 4° C.
  • FIG. 6 D depicts the stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at a pH of 37.5 at room temperature.
  • FIG. 6 E depicts the stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at a pH of 8.9 and a temperature of 4° C.
  • FIG. 6 F depicts the stability of GLP2-2G-10Nle-1K-Ex4-K5 (GLP2-K5) and GLP2-2G-1-EX4-L5A (GLP2-L5A) over 4 days at a pH of 8.9 at room temperature.
  • FIG. 7 A depicts the hepatic stability of long-acting GLP2-2G-1-EX4-L5A over 120 minutes.
  • FIG. 7 B depicts the hepatic stability of long-acting GLP2-2G-10Nle-1-EX4-L5A over 120 minutes.
  • FIG. 7 C depicts the hepatic stability of long-acting GLP2-2G-10Nle-1K-EX4-K5 over 120 minutes.
  • FIG. 8 depicts the mean plasma concentration of GLP2-2G-1-EX4-L5A over 96 hours in mice.
  • FIG. 9 depicts the mean plasma concentration of GLP2-2G-1-EX4-L5A over 504 hours in cyno monkeys.
  • FIG. 10 depicts the mean plasma concentration of GLP2-2G-10Nle-1-EX4-L5A over 96 hours in mice.
  • FIG. 11 depicts the mean plasma concentration of GLP2-2G-10Nle-1-EX4-L5A over 504 hours in cyno monkeys.
  • FIG. 12 depicts the mean plasma concentration of GLP2-2G-10Nle-1K-EX4-K5 over 96 hours in mice.
  • FIG. 13 depicts the mean plasma concentration of GLP2-2G-10Nle-1K-EX4-K5 over 504 hours in cyno monkeys.
  • FIG. 14 A depicts the normalized length of the small intestine in wildtype mice that received no treatment, GLP2-2G-1-L5A (GLP2-2G-1-EX4-L5A) and GLP2-2G-5-L5A (GLP2-2G-10Nle-1-EX4-L5A).
  • FIG. 14 B depicts the normalized length of the small intestine in wildtype mice that received no treatment, GLP2-2G-1-L5A (GLP2-2G-1-EX4-L5A) and GLP2-2G-5-L5A (GLP2-2G-10Nle-1-EX4-L5A).
  • FIG. 14 C depicts the bodyweight over 11 days of wildtype mice that received no treatment, GLP2-2G-1-L5A (GLP2-2G-1-EX4) and GLP2-2G-5-L5A (GLP2-2G-10Nle-1-EX4).
  • FIG. 15 A depicts the length of the small intestine in wildtype mice treated with GLP2-2G-10Nle-1K-EX4-K5 and untreated wildtype mice.
  • FIG. 15 B depicts the weight of the small intestine in wildtype mice treated with GLP2-2G-10Nle-1K-EX4-K5 and untreated wildtype mice.
  • FIG. 15 C depicts the length of the colon in wildtype mice treated with GLP2-2G-10Nle-1K-EX4-K5 and untreated wildtype mice.
  • FIG. 15 D depicts the weight of the colon in wildtype mice treated with GLP2-2G-10Nle-1K-EX4-K5 and untreated wildtype mice.
  • FIG. 16 A depicts the body weight over 12 days of mice with induced acute colitis that received no treatment, that were treated with GLP2-2G-1-L5A (GLP2-2G-1-EX4-L5), and with cyclosporin A.
  • FIG. 16 B depicts the normalized colon weight of mice with induced acute colitis that received no treatment, that were treated with GLP2-2G-1-L5A (GLP2-2G-1-EX4-L5), and with cyclosporin A.
  • FIG. 16 C depicts the normalized small intestine weight of mice with induced acute colitis that received no treatment, that were treated with GLP2-2G-1-L5A (GLP2-2G-1-EX4-L5), and with cyclosporin A.
  • FIG. 16 D depicts the crypt depth in the colon of wildtype mice and mice with induced acute colitis that received no treatment and that were treated with GLP2-2G-1-L5A (GLP2-2G-1-EX4-L5).
  • FIG. 16 E depicts the jejunum villi length of wildtype mice and mice with induced acute colitis that received no treatment and that were treated with GLP2-2G-1-L5A (GLP2-2G-1-EX4-L5).
  • FIG. 17 A depicts the body weight over 10 days of mice with induced acute colitis that received no treatment, GLP2-2G-10Nle-1K-EX4-K5, teduglutide, and cyclosporin A.
  • FIG. 17 B depicts the colon length of mice with induced acute colitis that received no treatment, GLP2-2G-10Nle-1K-EX4-K5, teduglutide, and cyclosporin A.
  • FIG. 17 C depicts the small intestine length of mice with induced acute colitis that received no treatment, GLP2-2G-10Nle-1K-EX4-K5, teduglutide, and cyclosporin A.
  • FIG. 17 D depicts the small intestine weight of mice with induced acute colitis that received no treatment, GLP2-2G-10Nle-1K-EX4-K5, teduglutide, and cyclosporin A.
  • FIG. 17 E depicts the height of the jejunum villi of mice with induced acute colitis that received no treatment, GLP2-2G-10Nle-1K-EX4-K5, teduglutide, and cyclosporin A.
  • FIG. 17 F depicts the proliferation index in the jejunum of mice with induced acute colitis that received no treatment, GLP2-2G-10Nle-1K-EX4-K5, teduglutide, and cyclosporin A.
  • FIG. 17 G depicts the pharmacokinetics of GLP2-2G-10Nle-1K-EX4-K5 and teduglutide in the mouse.
  • FIG. 18 A depicts the change in percent of bodyweight over 8 days of mice with induced acute colitis that received no treatment, GLP2-2G-10Nle-L5A, and cyclosporin A.
  • FIG. 18 B depicts the change in percent of bodyweight over 8 days of mice with induced acute colitis that received no treatment, GLP2-2G-1-EX4-L5A, and cyclosporin A.
  • FIG. 18 C depicts the change in percent of bodyweight over 8 days of mice with induced acute colitis that received no treatment, GLP2-2G-10Nle-1K-EX4-K5, cyclosporin A.
  • FIG. 18 D depicts the colon length of mice with induced acute colitis that received no treatment, that were treated with different long-acting GLP2R agonists, and cyclosporin A.
  • FIG. 18 E depicts the colon weight of mice with induced acute colitis that received no treatment, long-acting GLP2R agonists, and cyclosporin A.
  • FIG. 18 F depicts the small intestine length of mice with induced acute colitis that received no treatment, different long-acting GLP2R agonists, cyclosporin A.
  • FIG. 18 G depicts the small intestine weight of mice with induced acute colitis that received no treatment, different long-acting GLP2R agonists, and cyclosporin A.
  • FIG. 18 H depicts the gall bladder enlargement of mice with induced acute colitis that received no treatment, different long-acting GLP2R agonists, cyclosporin A.
  • FIG. 18 I depicts the amount of occult blood in the stool of mice with induced acute colitis that received no treatment, different long-acting GLP2R agonists, cyclosporin A.
  • FIG. 18 J depicts the pharmacokinetics of the long-acting GLP2R agonists at the 0.03 mg/kg dose.
  • FIG. 18 K depicts the pharmacokinetics of the long-acting GLP2R agonists at the 0.1 mg/kg dose.
  • FIG. 18 L depicts the pharmacokinetics of GLP2-2G-10Nle-L5A at both doses in an acute colitis mouse model.
  • FIG. 18 M depicts the pharmacokinetics of GLP2-2G-1-EX4-L5A at both doses in an acute colitis mouse model.
  • FIG. 18 N depicts the pharmacokinetics of GLP2-2G-10Nle-1K-EX4-K5 at both doses in an acute colitis mouse model.
  • FIG. 19 A depicts the absolute change in bodyweight of mice with induced chronic colitis that received no treatment, that were treated with GLP2-2G-1-EX4-L5A, that were treated with cyclosporin, and that were treated with teduglutide.
  • FIG. 19 B depicts the colon length of mice with induced chronic colitis that received no treatment, GLP2-2G-1-EX4-L5A, cyclosporin, and teduglutide.
  • FIG. 19 C depicts the colon weight of mice with induced chronic colitis that received no treatment, GLP2-2G-1-EX4-L5A, cyclosporin, and teduglutide.
  • FIG. 19 D depicts the small intestine weight of mice with induced chronic colitis that received no treatment, GLP2-2G-1-EX4-L5A, cyclosporin, and teduglutide.
  • FIG. 20 A depicts the colon length of mice with induced chronic colitis that received no treatment, GLP2-2G-10Nle-1-EX4-L5A, cyclosporin, and teduglutide.
  • FIG. 20 B depicts the colon weight of mice with induced chronic colitis that received no treatment, GLP2-2G-10Nle-1-EX4-L5A, cyclosporin, and teduglutide.
  • FIG. 20 C depicts the small intestine length of mice with induced chronic colitis that received no treatment, GLP2-2G-10Nle-1-EX4-L5A, cyclosporin, and teduglutide.
  • FIG. 21 A depicts serum levels of ALT in choline deficient mice that were untreated and that received GLP2-2G-5-EX4-L5A treatment, and in mice fed a normal diet.
  • FIG. 21 B depicts serum levels of AST in choline deficient mice that were untreated and that received GLP2-2G-5-EX4-L5A treatment, and in mice fed a normal diet.
  • FIG. 21 C depicts fibrosis scores in choline deficient mice that were untreated and that received GLP2-2G-5-EX4-L5A treatment, and in mice fed a normal diet.
  • FIG. 21 D depicts steatosis in choline deficient mice that were untreated and that received GLP2-2G-5-EX4-L5A treatment, and in mice fed a normal diet.
  • FIG. 21 E depicts lobular inflammation in choline deficient mice that were untreated and that received GLP2-2G-5-EX4-L5A treatment, and in mice fed a normal diet.
  • FIG. 22 A depicts the body weight of male mice weaned to a conventional diet that received no treatment, teduglutide, or GLP2-2G-10Nle-1K-EX4-K5.
  • FIG. 22 B depicts the body weight of female mice weaned to a conventional diet that received no treatment, teduglutide, or GLP2-2G-10Nle-1K-EX4-K5.
  • FIG. 22 C depicts the body weight of male mice weaned to a deficient diet that received no treatment, teduglutide, or GLP2-2G-10Nle-1K-EX4-K5.
  • FIG. 22 D depicts the body weight of female mice weaned to a deficient diet that received no treatment, teduglutide, or GLP2-2G-10Nle-1K-EX4-K5.
  • FIG. 22 E depicts the normalized small intestine weight of male mice weaned to a conventional diet that received no treatment, teduglutide, or GLP2-2G-10Nle-1K-EX4-K5.
  • FIG. 22 F depicts the normalized small intestine weight of female mice weaned to a conventional diet that received no treatment, teduglutide, or GLP2-2G-10Nle-1K-EX4-K5.
  • GLP-2 Glucagon-like peptide 2
  • GLP-2 is a hormone secreted from gut endocrine cells. GLP-2 stimulates intestinal growth, increases nutrient absorption and blood flow, decreases gut permeability and motility, and reduces epithelial cell apoptosis and inflammation. Due to the intestinotrophic effects of GLP-2, GLP-2 and related analogs may be useful for the treatment of GI disorders. In humans, the short plasma half-life of native GLP-2 requires higher doses and frequent injections or infusions to achieve a clinical efficacy, which can negatively affect patient compliance.
  • peptide conjugates comprising a peptide that modulates the GLP-2 receptor.
  • the peptide that modulates the GLP-2 receptor comprises two amino acids connected by a staple.
  • amino acids for use in conjugation include cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, homolysine, other sulfhydryl containing amino acids, or other amine containing amino acids.
  • the two amino acids are about or at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more amino acids apart.
  • the first amino acid has position i
  • the second amino acid has position i+7, i+11, i+13, i+15, or i+16.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i+n in the peptide, wherein n is 4-16.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i+7 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i+11 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i+15 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i+16 in the peptide.
  • peptide conjugates comprising a peptide that modulates the GLP-2 receptor.
  • a peptide that modulates the GLP-2 receptor is a GLP-2 receptor agonist.
  • the binding affinity of the peptide conjugate as described herein may be within about 5% of the binding affinity of an unmodified form of the GLP-2 peptide (e.g., the unconjugated GLP-2 peptide).
  • the binding affinity of the peptide conjugate as described herein may be within about 10% of the binding affinity of an unmodified form of the GLP-2 peptide.
  • the binding affinity of the peptide conjugate as described herein may be within about 15% of the binding affinity of an unmodified form of the GLP-2 peptide.
  • the binding affinity of the peptide conjugate as described herein may be within about 20% of the binding affinity of an unmodified form of the GLP-2 peptide.
  • the peptide that modulates the GLP-2 receptor may comprise at least a portion of a wild-type GLP-2 peptide and may comprise one or more amino acid mutations.
  • the one or more amino acid mutations may comprise a deletion, substitution, addition or a combination thereof.
  • the one or more amino acid mutations may comprise adding one or more amino acid residues to a wild-type GLP-2 peptide.
  • the one or more amino acid mutations may comprise deletion of one or more amino acid residues of the wild-type GLP-2 peptide.
  • the one or more amino acid mutations may comprise substitution of one or more amino acid residues of the wild-type GLP-2 peptide.
  • the one or more amino acid mutations may comprise substituting one or more amino acid residues of the wild-type GLP-2 peptide with one or more cysteine, lysine or other sulfhydryl or amine containing residues.
  • the one or more amino acid mutations may comprise substituting one or more amino acid residues of the wild-type GLP-2 peptide with one or more D-amino acid residues.
  • the one or more amino acid residues of the GLP-2 wild-type peptide may comprise one or more alanines, methionines, arginines, serines, threonines, and tyrosines.
  • the peptide that modulates the GLP-2 receptor may be modified with, for example, acetylation, phosphorylation, and methylation.
  • the peptide modification may comprise a chemical modification.
  • Peptide modifications may occur on the N-terminus of the peptide.
  • Peptide modifications may comprise acetyling the amino group at the N-terminus of the peptide.
  • peptide modifications may occur on the C-terminus of the peptide.
  • Peptide modifications may occur at one or more internal amino acids of the peptide.
  • Peptide modifications may comprise replacing the carboxyl group at the C-terminus of the peptide.
  • Peptide modifications may comprise modifying the carboxyl group at the C-terminus of the peptide.
  • the carboxyl group at the C-terminus of the peptide may be modified to produce an amide group.
  • the carboxyl group at the C-terminus of the peptide may be modified to produce an amine group.
  • Non-limiting examples of a peptide that modulates the GLP-2 receptor are shown in Table 1.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of any one of SEQ ID NOs: 1-40. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to any one of SEQ ID NOs: 1-40. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to any one of SEQ ID NOS: 1-40.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of any one of SEQ ID NOs: 1-9. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to any one of SEQ ID NOs: 1-9. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to any one of SEQ ID NOS: 1-9.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 1. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 1. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 1.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 2. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 2. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 2.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 3. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 3. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 3.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 4. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 4. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 4.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 5. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 5. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 5.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 6. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 6. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 6.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 7. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 7. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 7.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 8. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 8. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 8.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 9. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 9. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 9.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 10. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 10. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 10.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 11. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 11. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 11.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 12. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 12. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 12.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 13. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 13. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 13.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 14. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 14. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 14.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 15. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 15. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 15.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 16. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 16. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 16.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 17. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 17. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 17.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 19. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 19. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 19.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 20. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 20. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 20.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of any one of SEQ ID NOs: 21-29. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to any one of SEQ ID NOs: 21-29. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to any one of SEQ ID NOS: 21-29.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 21. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 21. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 21.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 2. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 22. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 22.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 23. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 23. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 23.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 24. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 24. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 24.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 25. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 25. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 25.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 26. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 26. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 26.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 27. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 27. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 27.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 28. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 28. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 28.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 29. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 29. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 29.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of any one of SEQ ID NOs: 30-40. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to any one of SEQ ID NOs: 30-40. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to any one of SEQ ID NOS: 30-40.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 31. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 31. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 31.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 32. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 32. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 32.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 33. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 33. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 33.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 34. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 34. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 34.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 35. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 35. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 35.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 36. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 36. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 36.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 37. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 37. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 37.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 38. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 38. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 38.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 39. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 39. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 39.
  • the peptide that modulates the GLP-2 receptor comprises an amino acid sequence of SEQ ID NO: 40. In some cases, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence at least about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to SEQ ID NO: 40. In some embodiments, the peptide that modulates the GLP-2 receptor comprises an amino acid sequence having up to about 1, 2, 3, 4, or 5 amino acid insertions, deletions, modifications, or substitutions as compared to SEQ ID NO: 40.
  • peptide conjugates comprising a staple.
  • the staple attached to the peptide is of Formula (I):
  • the staple attached to the peptide is of Formula (I):
  • A is optionally substituted alkylene.
  • A is —(CH 2 ) t —, wherein t is 1-12.
  • A is —(CH 2 ) t —, wherein t is 1-10.
  • A is —(CH 2 ) t —, wherein t is 1-8.
  • A is —(CH 2 ) t —, wherein t is 1-6.
  • A is —(CH 2 ) t —, wherein t is 1-4.
  • A is optionally substituted arylene. In some embodiments, A is arylene optionally substituted with halogen, alkyl, or haloalkyl. In some embodiments, A is arylene.
  • A is —NR 3 -alkylene-NR 3 —.
  • A is —N—.
  • X 1 and X 2 are identical. In some embodiments, X 1 and X 2 are different.
  • X 1 and X 2 are —C( ⁇ O)—. In some embodiments, X 1 and X 2 are independently -alkylene-C( ⁇ O)— or —C( ⁇ O)alkylene-. In some embodiments, X 1 and X 2 are independently —CH 2 —C( ⁇ O)— or —C( ⁇ O)—CH 2 —. In some embodiments, X 1 and X 2 are independently -alkylene-C( ⁇ O)NR 3 — or —C( ⁇ O)NR 3 -alkylene-.
  • X 1 and X 2 are independently —CH 2 —C( ⁇ O)NR 3 — or —C( ⁇ O)NR 3 —CH 2 —. In some embodiments, X 1 and X 2 are independently -alkylene-C( ⁇ O)NR 3 -alkylene- or -alkylene-NR 3 C( ⁇ O)-alkylene-. In some embodiments, X 1 and X 2 are independently —CH 2 —C( ⁇ O)NR 3 —CH 2 CH 2 — or —CH 2 —NR 3 C( ⁇ O)—CH 2 CH 2 —. In some embodiments, X 1 and X 2 are independently —CH 2 —C( ⁇ O)NH—CH 2 CH 2 — or —CH 2 —NHC( ⁇ O)—CH 2 CH 2 —.
  • each R 3 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments, each R 3 is hydrogen.
  • >A-R has the following structure:
  • r1 and r2 are each independently 0-4.
  • r1 and r2 are each independently 0-2. In some embodiments, r1 and r2 are each 0. In some embodiments, r1 and r2 are each 1. In some embodiments, r1 and r2 are each 3.
  • >A-R has the following structure:
  • >A-R has the following structure:
  • p1 is 1-3. In some embodiments, p1 is 1-2. In some embodiments, p1 is 1. In some embodiments, p1 is 2. In some embodiments, p1 is 3. In some embodiments, p1 is 4. In some embodiments, p1 is 5.
  • >A-R has the following structure:
  • >A-R has the following structure:
  • s is 1-15. In some embodiments, s is 1-10. In some embodiments, s is 5-15. In some embodiments, s is 5-10. In some embodiments, s is 5-20.
  • Y is hydrogen or —CO 2 H. In some embodiments, Y is hydrogen. In some embodiments, Y is —CO 2 H.
  • each L is independently —(CR 1 R 2 ) v —, -alkylene-O—, —C( ⁇ O)—, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; and v is 2-20.
  • each L is independently —(CR 1 R 2 ) v —, -alkylene-O—, —C( ⁇ O)—, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; and v is 2-16.
  • v is 2-16. In some embodiments, v is 2-5. In some embodiments, v is 5-16. In some embodiments, v is 5 or 16. In some embodiments, v is 2 or 16.
  • each R 1 or R 2 is independently hydrogen, halogen, —CN, —OW, —NR c R d , —C( ⁇ O)R b , —CO 2 R a , —C( ⁇ O)NR c R d , or C 1 -C 6 alkyl.
  • each R 1 or R 2 is independently hydrogen, halogen, —CO 2 R a , —C( ⁇ O)NR c R d , or C 1 -C 6 alkyl. In some embodiments, each R 1 or R 2 is independently hydrogen, —CO 2 R a , or —C( ⁇ O)NR c R d . In some embodiments, each R 1 or R 2 is independently hydrogen or —CO 2 R a .
  • the staple is N-(2-aminoethyl)
  • the staple attached to the peptide is
  • each L 1 is independently —(CR 1 R 2 ) v —, -alkylene-O—, —O-alkylene-, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—;
  • v is 2-20; and
  • s1 is 1-15.
  • the staple attached to the peptide is
  • each L 2 is independently —(CR 1 R 2 ) v —, -alkylene-O—, —O-alkylene-, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—;
  • v is 2-20; and
  • s2 is 1-15.
  • the staple attached to the peptide is
  • each L 3 is independently —(CR 1 R 2 ) v —, -alkylene-O—, —O-alkylene-, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s3 is 1-15.
  • the staple attached to the peptide is
  • each L 4 is independently —(CR 1 R 2 ) v —, -alkylene-O—, —O-alkylene-, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s4 is 1-15.
  • the staple attached to the peptide is
  • each L 5 is independently —(CR 1 R 2 ) v —, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s5 is 1-10.
  • the staple attached to the peptide is
  • each L 6 is independently —(CR 1 R 2 ) v —, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s6 is 1-5.
  • the staple attached to the peptide is
  • each L 7 is independently —(CR 1 R 2 ) v —, —C( ⁇ O)NR 3 —, or —NR 3 C( ⁇ O)—; v is 2-20; and s7 is 1-5.
  • the staple attached to the peptide is
  • L 8 is —(CR 1 R 2 ) v — and v is 10-20.
  • the staple attached to the peptide is
  • each L 9 is independently —(CR 1 R 2 ) v —, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s9 is 1-5.
  • the staple attached to the peptide is
  • L 10 is —(CR 1 R 2 ) v — and v is 10-20.
  • the staple attached to the peptide is
  • the staple attached to the peptide is
  • each L 11 is independently —(CR 1 R 2 ) v —, -alkylene-O—, —O-alkylene-, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s11 is 1-15.
  • the staple attached to the peptide is
  • each L 12 is independently —(CR 1 R 2 ) v —, -alkylene-O—, —O-alkylene-, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s12 is 1-15.
  • the staple attached to the peptide is
  • each L 13 is independently —(CR 1 R 2 ) v —, -alkylene-O—, —O-alkylene-, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s13 is 1-15.
  • the staple attached to the peptide is
  • each L 14 is independently —(CR 1 R 2 ) v —, -alkylene-O—, —O-alkylene-, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s14 is 1-15.
  • the staple attached to the peptide is
  • each L 15 is independently —(CR 1 R 2 ) v —, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s15 is 1-10.
  • the staple attached to the peptide is
  • each L 16 is independently —(CR 1 R 2 ) v —, —C( ⁇ O)NR 3 —, or —NR 3 C( ⁇ O)—; v is 2-20; and s16 is 1-5.
  • the staple attached to the peptide is
  • each L 17 is independently —(CR 1 R 2 ) v —, —C( ⁇ O)NR 3 —, or —NR 3 C( ⁇ O)—; v is 2-20; and s17 is 1-5.
  • the staple attached to the peptide is
  • L 18 is —(CR 1 R 2 ) v — and v is 10-20.
  • the staple attached to the peptide is
  • each L 19 is independently —(CR 1 R 2 ) v —, —C( ⁇ O)NR 3 —, —NR 3 C( ⁇ O)—, -alkylene-C( ⁇ O)NR 3 —, or -alkylene-NR 3 C( ⁇ O)—; v is 2-20; and s19 is 1-5.
  • the staple attached to the peptide is
  • L 20 is —(CR 1 R 2 ) v — and v is 10-20.
  • the staple attached to the peptide is:
  • the “ -S” being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue and the “ -NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • the staple attached to the peptide is:
  • n is 1-4 and m is 6-20; the “ -S” being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue and the “ -NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • the staple attached to the peptide is:
  • the “ -S” being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue and the “ -NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • the staple attached to the peptide is:
  • the “ -S” being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue.
  • the staple attached to the peptide is:
  • the “ -NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • the staple attached to the peptide is:
  • the “ -NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • the staple attached to the peptide is:
  • the “ -S” being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue.
  • the staple attached to the peptide is:
  • the “ -S” being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue.
  • the staple attached to the peptide is:
  • the “ -NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • the staple attached to the peptide is:
  • the “ -NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • Mechanisms by which peptide conjugates positively influence pharmacokinetic or pharmacodynamic behavior include, but are not limited to, (i) preventing or mitigating in vivo proteolytic degradation or other activity-diminishing chemical modification of the peptide that modulates the GLP-2 receptor; (ii) improving half-life or other pharmacokinetic properties by reducing renal filtration, decreasing receptor-mediated clearance or increasing bioavailability; (iii) reducing toxicity; (iv) improving solubility; and/or (v) increasing biological activity and/or target selectivity of the peptide or unmodified peptide.
  • Peptide conjugates may enhance one or more pharmacokinetic properties of a peptide that modulates the GLP-2 receptor when attached to the peptide.
  • Peptide conjugates disclosed herein may enhance the one or more pharmacokinetic properties of the peptide that modulates the GLP-2 receptor by at least about 200% as measured by pharmacodynamics when compared to the peptide or unmodified peptide alone.
  • Peptide conjugates disclosed herein may enhance the one or more pharmacokinetic properties of the therapeutic agent by at least about 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% as measured by pharmacodynamics when compared to the peptide or unmodified peptide alone.
  • the pharmacokinetic properties may comprise a half-life.
  • the half-life of the peptide conjugate may be at least about two-fold longer compared to the half-life of the unmodified peptide alone.
  • the half-life of the peptide conjugate disclosed herein may be at least about 3-fold, 4-fold, 5-fold, or 10-fold longer compared to the half-life of the therapeutic agent or unmodified therapeutic peptide alone.
  • the half-life of a peptide conjugate disclosed herein may be at least about 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, or 50-fold longer compared to the half-life of the unmodified peptide alone.
  • the half-life of the peptide conjugate is at least about 2-fold greater than the half-life of an unmodified form of the peptide. In some embodiments, the half-life of the peptide conjugate is at least about 5-fold greater than the half-life of an unmodified form of the peptide. In some embodiments, the half-life of the peptide conjugate is at least about 10-fold greater than the half-life of an unmodified form of the peptide.
  • a peptide conjugate as described herein may have a positive effect on terms of increasing manufacturability, and/or reducing immunogenicity of the peptide, compared to an unconjugated form of the unmodified therapeutic peptide.
  • peptide conjugates disclosed herein are useful for treating, alleviating, inhibiting and/or preventing one or more diseases and/or conditions.
  • the disease and/or condition may be a chronic disease or condition.
  • the disease and/or condition is an acute disease or condition.
  • the disease or condition may be recurrent, refractory, accelerated, or in remission.
  • the disease or condition may affect one or more cell types.
  • the one or more diseases and/or conditions may be an autoimmune disease, inflammatory disease, or metabolic disease.
  • the disease or condition may be diabetes or obesity, or a medical condition associated with diabetes or obesity.
  • the disease or condition may be non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or cardiovascular disease.
  • NAFLD non-alcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • the disease or condition may be an autoimmune disorder.
  • the disease or condition may be Crohn's disease or ulcerative colitis.
  • the disease or condition may be short bowel syndrome (SBS).
  • the disease or condition may be inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), or psoriasis.
  • the disease or condition may be Alzheimer's disease, Parkinson's disease or Huntington's disease.
  • the PLC may be administered with one or more additional therapeutic agents.
  • Disclosed herein are methods of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a composition disclosed herein comprising one or more peptide conjugates.
  • the metabolic disease or condition may be diabetes.
  • the metabolic disease or condition may be obesity.
  • the metabolic disease or condition may be glycogen storage disease, phenylketonuria, maple syrup urine disease, glutaric acidemia type 1, Carbamoyl phosphate synthetase I deficiency, alcaptonuria, Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD), acute intermittent porphyria, Lesch-Nyhan syndrome, lipoid congenital adrenal hyperplasia, congenital adrenal hyperplasia, POMPC deficiency, LEPR deficiency, Bardet Biedl syndrome, Alstrome syndrome, Prader-Willi Syndrome, Kearns-Sayre syndrome, Zellweger syndrome, Gaucher's disease, or Niemann Pick disease.
  • MCADD Medium-chain acyl-coenzyme A dehydrogenase deficiency
  • a method of preventing or treating NAFLD, NASH, or cardiovascular disease in a subject in need thereof comprising administering to the subject a peptide conjugate described herein.
  • SBS short bowel syndrome
  • IBD inflammatory bowel disease
  • IBS inflammatory bowel syndrome
  • psoriasis inflammatory bowel syndrome
  • a method of preventing or treating Crohn's disease or ulcerative colitis in a subject in need thereof comprising administering to the subject a peptide conjugate described herein.
  • a method of preventing or treating a sleep disorder is provided herein.
  • Provided herein is a method of preventing or treating chronic kidney disease (for example complication of diabetes).
  • Provided herein is a method of preventing or treating diabetic heart disease.
  • Provided herein is a method of preventing or treating cardiovascular events.
  • a method of preventing or treating Alzheimer's disease, Parkinson's disease or Huntington's disease in a subject in need thereof comprising administering to the subject a peptide conjugate described herein.
  • stomach and bowel-related disorders such as the treatment of neonatals with compromised intestine function, osteoporosis, and DPP-IV (dipeptidylpeptidase-IV) mediated conditions.
  • the stomach and bowel-related disorders include ulcers, gastritis, digestion disorders, malabsorption syndromes, short-gut syndrome, cul-de-sac syndrome, inflammatory bowel disease, celiac sprue (for example arising from gluten induced enteropathy or celiac disease), tropical sprue, hypogammaglobulinemia sprue, enteritis, regional enteritis (Crohn's disease), ulcerative colitis, irritable bowel syndrome associated with diarrhea, Small intestine damage and short bowel syndrome.
  • celiac sprue for example arising from gluten induced enteropathy or celiac disease
  • tropical sprue tropical sprue
  • hypogammaglobulinemia sprue enteritis
  • enteritis enteritis
  • Crohn's disease ulcerative colitis
  • irritable bowel syndrome associated with diarrhea Small intestine damage and short bowel syndrome.
  • a method of preventing or treating radiation enteritis, infectious or post-infectious enteritis, and small intestinal damage due to toxic or other chemotherapeutic agents may require administration of the peptide conjugate prior to, concurrently with or following a course of chemotherapy or radiation therapy in order to reduce side effects of chemotherapy such as diarrhea, abdominal cramping and vomiting, and reduce the consequent structural and functional damage of the intestinal epithelium resulting from the chemotherapy or radiation therapy.
  • a method of preventing or treating malnutrition for example conditions such as the wasting syndrome cachexia and anorexia.
  • a method of preventing or treating a disease or condition which benefits from a modulator of a GLP-2 receptor in a subject in need thereof comprising administering to the subject a peptide conjugate described herein.
  • compositions comprising a peptide conjugate described herein and one or more additional therapeutic agents.
  • the additional therapeutic agents may comprise one or more other diabetes drugs, DPP4 inhibitors, SGLT2 inhibitors, hypoglycemic drugs and biguanidine drugs, insulin secretogogues and sulfonyl urea drugs, TZD drugs, insulin and insulin analogs, FGF21 and analogs, leptin or leptin analogs, amylin and amylin analogs, an anti-inflammatory drug, cyclosporine A or FK506, 5-ASA, or a statin, or any combination thereof.
  • the additional therapeutic agent may be aspirin.
  • the additional therapeutic agents may comprise a therapeutic incretin or derivative thereof.
  • incretins or derivatives thereof include GLP-1, glucagon, oxyntomodulin, exendin-4, GLP-2, GIP, and combinations thereof.
  • compositions comprising a peptide conjugate described herein and a pharmaceutically acceptable excipients or vehicles.
  • Pharmaceutically acceptable excipients or vehicles may include carriers, excipients, diluents, antioxidants, preservatives, coloring, flavoring and diluting agents, emulsifying agents, suspending agents, solvents, fillers, bulking agents, buffers, delivery vehicles, tonicity agents, cosolvents, wetting agents, complexing agents, buffering agents, antimicrobials, and surfactants.
  • Neutral buffered saline or saline mixed with serum albumin are exemplary appropriate carriers.
  • the pharmaceutical compositions may include antioxidants such as ascorbic acid; low molecular weight polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as Tween, pluronics, or polyethylene glycol (PEG).
  • antioxidants such as ascorbic acid
  • low molecular weight polypeptides such as serum albumin, gelatin, or immunoglobulins
  • hydrophilic polymers such as polyviny
  • suitable tonicity enhancing agents include alkali metal halides (preferably sodium or potassium chloride), mannitol, sorbitol, and the like.
  • Suitable preservatives include benzalkonium chloride, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid and the like. Hydrogen peroxide also may be used as preservative.
  • Suitable cosolvents include glycerin, propylene glycol, and PEG.
  • Suitable complexing agents include caffeine, polyvinylpyrrolidone, beta-cyclodextrin or hydroxy-propyl-beta-cyclodextrin.
  • Suitable surfactants or wetting agents include sorbitan esters, polysorbates such as polysorbate 80, tromethamine, lecithin, cholesterol, tyloxapal, and the like.
  • the buffers may be conventional buffers such as acetate, borate, citrate, phosphate, bicarbonate, or Tris-HCl.
  • Acetate buffer may be about pH 4-5.5, and Tris buffer can be about pH 7-8.5. Additional pharmaceutical agents are set forth in Remington's Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, ed., Mack Publishing Company, 1990.
  • the composition may be in liquid form or in a lyophilized or freeze-dried form and may include one or more lyoprotectants, excipients, surfactants, high molecular weight structural additives and/or bulking agents.
  • a lyoprotectant is included, which is a non-reducing sugar such as sucrose, lactose or trehalose.
  • the amount of lyoprotectant generally included is such that, upon reconstitution, the resulting formulation will be isotonic, although hypertonic or slightly hypotonic formulations also may be suitable.
  • the amount of lyoprotectant should be sufficient to prevent an unacceptable amount of degradation and/or aggregation of the protein upon lyophilization.
  • Exemplary lyoprotectant concentrations for sugars (e.g., sucrose, lactose, trehalose) in the pre-lyophilized formulation are from about 10 mM to about 400 mM.
  • a surfactant is included, such as for example, nonionic surfactants and ionic surfactants such as polysorbates (e.g., polysorbate 20, polysorbate 80); poloxamers (e.g., poloxamer 188); poly(ethylene glycol) phenyl ethers (e.g., Triton); sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- or stearyl-sarcosine; linoleyl, myristyl-
  • High molecular weight structural additives may include for example, acacia, albumin, alginic acid, calcium phosphate (dibasic), cellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, dextran, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polyme
  • compositions may be suitable for parenteral administration.
  • Exemplary compositions are suitable for injection or infusion into an animal by any route available to the skilled worker, such as intraarticular, subcutaneous, intravenous, intramuscular, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, or intralesional routes.
  • a parenteral formulation typically may be a sterile, pyrogen-free, isotonic aqueous solution, optionally containing pharmaceutically acceptable preservatives.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringers' dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like.
  • Preservatives and other additives may also be present, such as, for example, anti-microbials, anti-oxidants, chelating agents, inert gases and the like. See generally, Remington's Pharmaceutical Science, 16th Ed., Mack Eds., 1980.
  • compositions described herein may be formulated for controlled or sustained delivery in a manner that provides local concentration of the product (e.g., bolus, depot effect) and/or increased stability or half-life in a particular local environment.
  • the compositions can include the formulation of peptide conjugates, disclosed herein with particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc., as well as agents such as a biodegradable matrix, injectable microspheres, microcapsular particles, microcapsules, bioerodible particles beads, liposomes, and implantable delivery devices that provide for the controlled or sustained release of the active agent which then can be delivered as a depot injection.
  • Such sustained- or controlled-delivery means are known and a variety of polymers have been developed and used for the controlled release and delivery of drugs.
  • Such polymers are typically biodegradable and biocompatible.
  • Polymer hydrogels including those formed by complexation of enantiomeric polymer or polypeptide segments, and hydrogels with temperature or pH sensitive properties, may be desirable for providing drug depot effect because of the mild and aqueous conditions involved in trapping bioactive protein agents (e.g., antibodies comprising an ultralong CDR3).
  • Suitable and/or preferred pharmaceutical formulations may be determined in view of the present disclosure and general knowledge of formulation technology, depending upon the intended route of administration, delivery format, and desired dosage. Regardless of the manner of administration, an effective dose may be calculated according to patient body weight, body surface area, or organ size. Further refinement of the calculations for determining the appropriate dosage for treatment involving each of the formulations described herein are routinely made in the art and is within the ambit of tasks routinely performed in the art. Appropriate dosages may be ascertained through use of appropriate dose-response data.
  • Alkyl refers to a straight or branched chain hydrocarbon monoradical, which may be fully saturated or unsaturated, having from one to about ten carbon atoms, or from one to six carbon atoms, wherein a sp3-hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • saturated hydrocarbon monoradical examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl,
  • C 1 -C 6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C 1 -C 3 alkyl, a C 1 -C 2 alkyl, or a C 1 alkyl.
  • alkyl refers to an unsaturated straight or branched chain hydrocarbon monoradical it is known as an “alkenyl” or an “alkynyl”.
  • alkenyl may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • alkenyls include, but are not limited to ethenyl (—CH ⁇ CH 2 ), 1-propenyl (—CH 2 CH ⁇ CH 2 ), isopropenyl [—C(CH 3 ) ⁇ CH 2 ], butenyl, 1,3-butadienyl and the like.
  • C 2 -C 6 alkenyl means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • the alkenyl is a C 2 -C 10 alkenyl, a C 2 -C 9 alkenyl, a C 2 -C 8 alkenyl, a C 2 -C 7 alkenyl, a C 2 -C 6 alkenyl, a C 2 -C 5 alkenyl, a C 2 -C 4 alkenyl, a C 2 -C 3 alkenyl, or a C 2 alkenyl.
  • alkynyl include, but are not limited to ethynyl, 2-propynyl, 2- and the like.
  • C 2 -C 6 alkynyl means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • the alkynyl is a C 2 -C 10 alkynyl, a C 2 -C 9 alkynyl, a C 2 -C 8 alkynyl, a C 2 -C 7 alkynyl, a C 2 -C 6 alkynyl, a C 2 -C 5 alkynyl, a C 2 -C 4 alkynyl, a C 2 -C 3 alkynyl, or a C 2 alkynyl.
  • an alkyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
  • the alkyl is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Whenever it appears herein, a numerical range such as “C 1 -C 6 alkylene” means that the alkylene consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkylene” where no numerical range is designated.
  • the alkylene is a C 1 -C 10 alkylene, a C 1 -C 9 alkylene, a C 1 -C 8 alkylene, a C 1 -C 7 alkylene, a C 1 -C 6 alkylene, a C 1 -C 5 alkylene, a C 1 -C 4 alkylene, a C 1 -C 3 alkylene, a C 1 -C 2 alkylene, or a C 1 alkylene.
  • an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkylene is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
  • an alkylene is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe.
  • the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula —OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 . In some embodiments, an alkoxy is optionally substituted with oxo, halogen, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from a hydrocarbon ring system comprising hydrogen, 6 to 30 carbon atoms and at least one aromatic ring.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6- to 10-membered aryl.
  • the aryl is a 6-membered aryl.
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the aryl is phenyl.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
  • an aryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Cycloalkyl refers to a stable, partially or fully saturated, monocyclic or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (C 3 -C 15 cycloalkyl), from three to ten carbon atoms (C 3 -C 10 cycloalkyl), from three to eight carbon atoms (C 3 -C 8 cycloalkyl), from three to six carbon atoms (C 3 -C 6 cycloalkyl), from three to five carbon atoms (C 3 -C 5 cycloalkyl), or three to four carbon atoms (C 3 -C 4 cycloalkyl).
  • the cycloalkyl is a 3- to 6-membered cycloalkyl.
  • the cycloalkyl is a 5- to 6-membered cycloalkyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls or carbocycles include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Halo or “halogen” refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.
  • Heterocycloalkyl refers to a stable 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur.
  • Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl), from two to ten carbon atoms (C 2 -C 10 heterocycloalkyl), from two to eight carbon atoms (C 2 -C 8 heterocycloalkyl), from two to six carbon atoms (C 2 -C 6 heterocycloalkyl), from two to five carbon atoms (C 2 -C 5 heterocycloalkyl), or two to four carbon atoms (C 2 -C 4 heterocycloalkyl).
  • the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholiny
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides and the oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring).
  • Partially saturated heterocycloalkyls include, for example dihydropyrrolyl or tetrahydropyridine.
  • a heterocycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
  • a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • a heteroalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe.
  • the heteroalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5- to 14-membered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furany
  • a heteroaryl is optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, —OMe, —NH 2 , or —NO 2 .
  • a heteroaryl is optionally substituted with halogen, methyl, ethyl, —CN, —CF 3 , —OH, or —OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • percent identity refers to a comparison between two nucleic acid or amino acid sequences. Such comparisons are measured using any number of alignment methods known in the art, including but not limited to global (e.g., Needleman-Wunsch algorithm) or local alignments (e.g., Smith-Waterman, Sellers, or other algorithm). Percent identity often refers to the percentage of matching positions of two sequences for a contiguous section of positions, wherein the two sequences are aligned in such a way to maximize matching positions and minimize gaps of non-matching positions. In some instances, alignments are conducted wherein there are no gaps between the two sequences. In some instances, the alignment results in less than 5% gaps, less than 3% gaps, or less than 1% gaps. Additional methods of sequence comparison or alignment are also consistent with the disclosure.
  • the percent homology between the two sequences may be a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences.
  • the length of a sequence aligned for comparison purposes may be at least about: 30%, 40%, 50%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 95%, of the length of the reference sequence.
  • a BLAST® search may determine homology between two sequences. The homology can be between the entire lengths of two sequences or between fractions of the entire lengths of two sequences.
  • the two sequences can be peptide sequences, amino acid sequences, or fragments thereof.
  • the actual comparison of the two sequences can be accomplished by well-known methods, for example, using a mathematical algorithm.
  • a non-limiting example of such a mathematical algorithm may be described in Karlin, S. and Altschul, S., Proc. Natl. Acad. Sci. USA, 90-5873-5877 (1993). Such an algorithm may be incorporated into the NBLAST and XBLAST programs (version 2.0), as described in Altschul, S. et al., Nucleic Acids Res., 25:3389-3402 (1997).
  • any relevant parameters of the respective programs e.g., NBLAST
  • any relevant parameters of the respective programs e.g., NBLAST
  • Other examples include the algorithm of Myers and Miller, CABIOS (1989), ADVANCE, ADAM, BLAT, and FASTA.
  • the percent identity between two amino acid sequences can be accomplished using, for example, the GAP program in the GCG software package (Accelrys, Cambridge, UK).
  • “Pharmaceutically acceptable” refers to approved or approvable by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, including humans.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • “Pharmaceutically acceptable excipient, carrier or adjuvant” refers to an excipient, carrier or adjuvant that may be administered to a subject, together with at least one antibody of the present disclosure, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient, or carrier with which at least one antibody of the present disclosure is administered.
  • Treating” or “treatment” or “to treat” or “alleviating” or “to alleviate” may refer to: 1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder; and/or 2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • Treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology.
  • Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, and diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • those in need of treatment may include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, gamma-carboxyglutamate, and O-phosphoserine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, e.g., an alpha carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
  • Such analogs can have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions similarly to a naturally occurring amino acid.
  • “Disorder” or “disease” refers to a condition that would benefit from treatment with a substance/molecule (e.g., a peptide conjugate as disclosed herein) or method disclosed herein. This includes chronic and acute disorders or diseases including those pathological conditions which predispose the mammal to the disorder in question.
  • “Mammal” for purposes of treatment refers to any animal classified as a mammal, including humans, rodents (e.g., mice and rats), and monkeys; domestic and farm animals; and zoo, sports, laboratory, or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats, rabbits, etc.
  • the mammal is selected from a human, rodent, or monkey.
  • Unmodified peptide refers to either an unmodified sequence (wild type peptide) or a modified sequence without a staple.
  • Peptides were synthesized by standard solid-phase peptide synthesis (SPPS) techniques and purified via HPLC (as described).
  • Flash chromatography purifications were performed on silica gel prepacked columns (40 ⁇ m, RediSep® Rf from Teledyne Isco) on a CombiFlash® Rf (Teledyne Isco). Purified final compounds were eluted as single and symmetrical peaks (thereby confirming a purity of ⁇ 95%).
  • High resolution mass spectra were recorded on an Agilent 1200 Series Accurate Mass Time-of-Flight (TOF) with an Aeris Widepore column (XB-C8, 3.6 ⁇ m particle size, 150 ⁇ 2.1 mm, flow: 0.5 mL/min).
  • Solvents A—H 2 O+0.1% formic acid, B—MeCN+0.1% formic acid, gradient: 0-2 min 5% B, 2-12 min 5-60% B, 12-13 min 60-80% B, 13-14 min 80-20% B, 14-15 min 20-80% B, 15-16 min 80-20% B, 16-17 min 20-95% B, 17-20 min 95% B, 20-21 min 95-5% B.
  • Fmoc-Lys(ivDde)-OH 60 mg, 100 ⁇ mol was coupled to 2-chlorotrityl chloride resin (Novabiochem) (100 mg, 80 ⁇ mol) by mixing the amino acid, resin, and DIEA (70 ⁇ L, 400 ⁇ mol) in 5 mL of DMF and stirring for 30 min. The resin was then washed with DMF (3 ⁇ ), DCM (3 ⁇ ) and treated with CH 3 OH/DCM/DIEA (8:1:1) for 10 min to cap the unreacted trityl chloride sites, dried under vacuum and stored in a desiccator.
  • 2-chlorotrityl chloride resin Novabiochem
  • the resin was treated with 2% hydrazine in DMF (5 mL, 2 ⁇ 15 min). Positive ninhydrin and/or TNBS test was observed. The resin was then washed with DMF (3 ⁇ ), DCM (3 ⁇ ).
  • the resin was then treated with bromoacetic anhydride (2.4 eq), and DIEA (2.6 eq) in 200 mL of DCM for 30 min.
  • the resin was washed with DCM (3 ⁇ ), the product was cleaved from the resin using 5 mL of 10% TFA in DCM containing 10% H 2 O and 10% triisopropylsilane for 1 h.
  • Myristic acid (184 mg, 0.805 mmol, 1 eq) was dissolved in 4 mL of DMF.
  • HATU (321 mg, 0.845 mmol, 1.1 eq)
  • DIEA 154 ⁇ L, 0.885 mmol, 1.1 eq
  • Boc-NH-PEG 2 -COOH 200 mg, 0.805 mmol, 1 eq
  • the reaction mixture was then stirred for 1.5 h, and the solvent was removed.
  • the product was dissolved in EtOAc.
  • the organic layer was successively washed with 1M HCl, sat. NaHCO 3 , and brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • Octadecanedioic acid mono-tert-butyl ester acid 200 mg, 0.54 mmol, 1 eq was dissolved in 5 mL of DMF.
  • HATU 225 mg, 0.59 mmol, 1.1 eq
  • DIEA 103 ⁇ L, 0.59 mmol, 1.1 eq
  • the reaction mixture was then stirred for 3 h, and the solvent was removed.
  • the product was dissolved in EtOAc.
  • the organic layer was successively washed with sat.
  • Palmitic acid (235 mg, 0.919 mmol, 1.05 eq) was dissolved in 4 mL of DMF.
  • HATU (349 mg, 0.919 mmol, 1.05 eq) and DIEA (167 ⁇ L, 0.963 mmol, 1.1 eq) were added followed by the addition of Boc-NH-PEG 2 -NH 2 (200 mg, 0.875 mmol, 1 eq).
  • the reaction mixture was then stirred for 2 h, and the solvent was removed.
  • the product was dissolved in EtOAc.
  • the organic layer was successively washed with 1M HCl, sat.
  • hexadecanedioic acid mono tert-butyl ester 102 mg, 0.30 mmol, 1 eq
  • DMF 5 mL
  • HATU 125 mg, 0.33 mmol 1.1 eq
  • DIEA 51 ⁇ L, 0.33 mmol, 1.1 eq
  • compound L4b 151.9 mg, 0.3 mmol, 1 eq
  • the reaction mixture was agitated 3 h at RT.
  • the product was diluted with EtOAc.
  • the organic layer was successively washed with 1M HCl, sat. NaHCO 3 , brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • octadecanedioic acid mono tert-butyl ester (281 mg, 0.76 mmol, 1 eq) dissolved in DMF (5 mL) was added HATU (288 mg, 0.76 mmol, 1 eq), DIEA (132 ⁇ L, 0.76 mmol, 1 eq) and compound L16b (351 mg, 0.76 mmol, 1 eq) dissolved in 1 mL of DMF.
  • the reaction mixture was agitated 3 h at RT.
  • the product was diluted with EtOAc.
  • the organic layer was successively washed with 1M HCl, sat. NaHCO 3 , brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • octadecanedioic acid mono tert-butyl ester 225 mg, 0.61 mmol, 1 eq
  • DMF 5 mL
  • HATU 231 mg, 0.61 mmol 1 eq
  • DIEA 106 ⁇ L, 0.61 mmol, 1 eq
  • compound L17b 335 mg, 0.61 mmol, 1 eq
  • the reaction mixture was agitated 2 h at RT.
  • the product was diluted with EtOAc.
  • the organic layer was successively washed with 1M HCl, sat. NaHCO 3 , brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • Peptides were dissolved at a concentration of 2 mM with 1.5 eq of bromoacetyl staple in 1:3 (v/v) MeCN/30 mM NH 4 HCO 3 buffer (pH 8.5).
  • the pH of the reaction mixture was readjusted with ammonium hydroxide to correct the drop in pH caused by the peptide TFA counterion. More MeCN was added for particularly insoluble peptides.
  • the reaction was stirred at RT for 2-4 h, before acidification to pH 5 via dropwise addition of acetic acid. The resulting solution was lyophilized and purified by reversed-phase HPLC.
  • Peptide-resin bearing amine side chain orthogonal protection (Dde/Mmt) at each stapling position was swollen in DMF for 1 h.
  • the Dde protecting group was removed from the first side chain via treatment with 2% hydrazine solution in DMF (2 ⁇ 15 min). Positive TNBS test was observed.
  • the linker building block specified below was coupled as described and a negative TNBS test was observed.
  • the solvent was exchanged for DCM and the Mint group was removed from the second side chain via treatment with 1% TFA in DCM containing 5% TIPS, 5 ⁇ 2 min.
  • the resin was washed with DCM, 10% DIEA in DMF, DMF and a positive TNBS test was observed.
  • the linker was cyclized and the PEG-fatty acid portion of the staple (if applicable) elongated as described below.
  • the complete stapled peptide was cleaved from the resin using 95% TFA, 2.5% TIPS, 2.5% H 2 O, 3 h.
  • the peptide cleavage mixture was evaporated to an oil, triturated and washed with diethyl ether and purified via reversed-phase HPLC.
  • a Dde/Alloc protection scheme can also be used for this approach, which requires the addition of allyl alcohol to the Dde deprotection cocktail as a scavenger to prevent concurrent reduction of the Alloc allyl moiety.
  • linker coupling the intramolecular symmetric anhydride of building block K(Fmoc) linker (2 eq) was preformed using DIC (2 eq) and catalytic DMAP in dry DCM for 10 min at RT. The peptide-resin solvent was exchanged for DCM and the anhydride was then added and agitated overnight. The resin was drained, washed with DCM and DMF. The linker was cyclized overnight via treatment with DIC (1 eq) and HOBt or HOAt (1 eq) in DMF, and a negative TNBS was observed. Remaining uncyclized linker was capped via treatment with 10% acetic anhydride in DMF (30 min).
  • the linker Fmoc group was deprotected via treatment with 20% piperidine in DMF (2 ⁇ 10 min). A positive TNBS was observed. Subsequent staple PEG and fatty acid building blocks were attached sequentially to the linker free amine via standard coupling chemistry: building block (3 eq), HATU (3 eq) and DIEA (6 eq) in DMF, 1 h at RT, using 20% piperidine in DMF for deprotection cycles (5+10 min, RT).
  • A(Fmoc) linker (2 eq) was attached using HATU (4 eq) and DIEA (4 eq) in DMF, 1 ⁇ 2 h.
  • the cyclization step was achieved using HATU (1 eq) and DIEA (2 eq) in DMF, 1 ⁇ 2 h.
  • Remaining uncyclized linker was capped via treatment with 10% acetic anhydride in DMF (30 min).
  • the linker Fmoc group was deprotected via treatment with 20% piperidine in DMF (2 ⁇ 10 min). It was not possible to observe a positive TNBS test for the aniline nitrogen.
  • Fmoc-R-Ala-OH (3 eq) was coupled using HATU (3 eq) and DIEA (6 eq) in DMF, 4 ⁇ 1 h at RT or as the symmetric anhydride using DIC/DMAP in DCM (2 h, RT). Subsequent staple PEG and fatty acid building blocks were attached sequentially to the linker free amine via standard coupling chemistry: building block (3 eq), HATU (3 eq) and DIEA (6 eq) in DMF, 1 h at RT, using 20% piperidine in DMF for deprotection cycles (5+10 min, RT).
  • the peptide conjugate described herein comprises a staple of Table 2.
  • the “ -S” being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue
  • the “ -NH” being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • the peptide conjugate described herein is as shown in Table 3.
  • HGDGSFSDEVNTILDNCA 17, 24 L5A ARDFICWLIQTKITD (SEQ ID NO. 27) 33 HGDGSFSDCMNTILDCLA 9, 16 L5A ARDFINWLIQTKITD (SEQ ID NO. 28) 34 HGDGSFSDCMNTILDCLA 9, 16 L4A ARDFINWLIQTKITD (SEQ ID NO. 28) 35 HGDGSFSDEMCTILDNLC 11, 18 L5A ARDFINWLIQTKITD (SEQ ID NO. 29) 36 HGDGSFSDE(Nle)NTILDN 17, 24 K5 KAARDFIKWLIQTKITD (SEQ ID NO.
  • HGDGSFSDE(Nle)(D- 17, 24 K5 Phe)TILDNKAARDFIKWLI QTKITD (SEQ ID NO. 31) 38 HGDGSFSDE(Nle)NSLLDN 17, 24 K5 KAARDFIKWLIQTKITD (SEQ ID NO. 32) 39 HGDGSFSDE(Nle)NTA(Nle) 17, 24 K5 DNKAARDFIKWLIQTKIT D (SEQ ID NO. 33) 40 HGDGSFSDE(Nle)NT(Nle) 17, 24 K5 (Nle)DNKAARDFIKWLIQT KITD (SEQ ID NO.
  • GLP-2R activation Peptide activity and potency toward the GLP-2R activation were determined using a stable HEK293 cell line overexpressing cAMP response element (CRE) driven luciferase reporter and human GLP-2R in the presence of LP2 FBS.
  • CRE cAMP response element
  • GLP2-2G teduglutide
  • HEK293-GLP-2R-CRE cells were seeded in 384-well plates at a density of 5000 cells per well and cultured for 18 h in DMEM with 10% FBS at 37° C. and 5% CO2. Cells were treated with peptides in a dose dependent manner for 16 h, and receptor activation was reported by luminescence intensities, using One-Glo (Promega, WI) luciferase reagent following manufacturer's instruction. The EC50 of each peptide was determined using GraphPad Prism 6 software (GraphPad, San Diego, Calif.). The assay was performed in triplicate, and the results were obtained in three independent experiments. The results are shown in Table 4 below.
  • the estimated terminal half-lives after iv or sc administration is shown in Table 5 below.
  • Example C The In Vitro Potency of the Long-Acting GLP2R Agonists to Human GLP2R
  • This example assessed the potency of the long-acting GLP2s on GLP2R.
  • GLP2-2G (teduglutide) was used as a positive control. As concentrations of teduglutide increased, the ratio of 665/615 decreased, indicating increased activity of GLP2R, as depicted in FIG. 1 A . Varying the concentration of GLP2-2G-10Nle-1K-EX4-K5, GLP2-2G-1-EX4-L5A and GLP2-2G-10Nle-1-EX4-L5A produced similar activity levels when compared to teduglutide. From this data, IC 50 values were calculated as seen in Table 6. When 10% fetal bovine serum was added to the assay, the teduglutide curve became steeper than the curve of the long-acting GP2R agonists, as depicted in FIG. 1 B . The resulting IC 50 values were higher for all three long-acting GLP2R agonists, as listed in Table 6.
  • Example D The In Vitro Potency of the Long-Acting GLP2R Agonists on Mouse GLP2R
  • the ratio of 665 fluorescence to 615 fluorescence was plotted against the concentration of the molecule, as depicted in FIG. 2 , and this data was used to calculate the IC 50 values, listed in Table 7.
  • Teduglutide (GLP2-2G) and apraglutide (a synthetic GLP-2 analog) were used as positive controls.
  • the IC 50 values of the long-acting GLP2R agonists were found to be in similar ranges as that of both teduglutide and apraglutide, indicating that the long-acting GLP2R agonists were relatively potent agonists to the mouse GLP2R.
  • Example E The In Vitro Potency of the Long-Acting GLP2R Agonists on Cyno Monkey GLP2R
  • the ratio of 665 to 615 was plotted against the concentration in nM, as depicted in FIG. 3 , in order to determine the potency of the long-acting GLP2R agonists on cyno monkey GLP2R.
  • the EC 50 was calculated using the data in FIG. 3 and the values are listed in Table 8.
  • the EC50 value for the long-acting GLP2R agonists were within a range of 0.119 nM to 0.156 nM, indicating that the long-acting GLP2R agonists were relatively potent agonists to the cyno GLP2R.
  • Example F The Long-Acting GLP2R Agonists were Highly Selective for GLP2R Over Other G-Protein Coupled Receptors
  • This example assessed the effect of the stabilized GLP2R agonists on other G-protein coupled receptors (GPCRs).
  • GLP2 nor either stabilized molecule tested produced any significant change in the activity levels of GLP-1R, when compared to the change produced by varying concentrations of semaglutide, a GLP-1R agonist, as depicted in FIG. 4 A .
  • IC 50 values were calculated, as listed in Table 9, the values were extremely high when compared to semaglutide, the positive control. This indicated that extremely high concentrations of GLP2 and the long-acting GLP2R agonists were required before GLP-1R was activated.
  • GLP-2 >500 >500 >500
  • GLP2-2G-10Nle-1-L5A >500 >500 >500 >500
  • the long-acting GLP2R agonists did not result in a change in GCGR activity levels over a range of concentrations between 10 ⁇ 2 and 10 2 nm, as depicted in FIG. 4 B .
  • increasing concentrations of glucagon impacted activity levels of GCGR.
  • glucagon had an IC 50 of 0.04 indicating it affected the activity levels of GCGR at lower concentrations, the IC 50 values for GLP2 and the long-acting GLP2R agonists were greater than 500, as listed in Table 9.
  • GLP2-2G-1-EX4-L5A and GLP2-2G-10Nle-1K-EX4-K5 were profiled against the gpcrMAX Panel by DiscoverRx.
  • 168 GPCR targets were tested with an agonist and antagonist primary screen. The assays were performed utilizing the PathHunter beta-arrestin enzyme fragment complementation (EFC) technology. In agonist mode, no targets were identified with >30% activity except for GLP2. In antagonist mode: no targets were identified with >35% inhibition.
  • EFC PathHunter beta-arrestin enzyme fragment complementation
  • Example G The Stability of the Long-Acting GLP2R Agonists at Different Temperatures
  • This example assessed the stability of the stabilized GLP2R agonists at different temperatures over extended periods of time.
  • GLP2-2G-1-EX4-L5A GLP2-L5A
  • GLP2-2G-10Nle-1K-EX4-L5A GLP2-K5A
  • FIG. 5 A At 25° C. 3% oxidation was observed for GLP2-2G-1-EX4-L5A, while GLP2-2G-10Nle-1K-EX4-K5 stayed reasonably intact for 4 days, as depicted in FIG. 5 B .
  • 11% oxidation was observed for GLP2-2G-1-EX4-L5A and a 4% increase in the +12 Da impurity at day 2.
  • GLP2-2G-10Nle-1K-EX4-K5 had a higher percentage of intact peptide at 4 days than GLP2-2G-1-EX4-L5A, as depicted in FIG. 5 C .
  • GLP2-2G-10Nle-1K-EX4-K5 had a higher percentage of intact peptide at 4 days than GLP2-2G-1-EX4-L5A, as depicted in FIG. 5 C .
  • At 70° C. force degradation
  • many racemized products for both peptides were present.
  • the percent of intact peptides was less than 50% for both GLP2-2G-1-EX4-L5A and GLP2-2G-10Nle-1K-EX4-K5, as depicted in FIG. 5 D .
  • Example H The Stability of the Long-Acting GLP2R Agonists in Different Solutions
  • Example E The Long-Term Stability of the Thioether Peptides in Liquid and in Solid Forms
  • the stability of the thioether peptides was measured against wet air oxidation. Met oxidation was observed for GLP2-2G-1-EX4-L5A after 10 days, with 16% degradation observed. GLP2-2G-10Nle-1-EX4-L5A was more stable against wet air oxidation. This indicated that the thioether bridge was stable against oxidation for at least 10 days.
  • the powder was stored at 4 C as an HCl salt. There was no sign of Met oxidation for GLP2-2G-1-EX4-L5A (GLP2-L5A) after 4 months. Likewise, there was no sign of Met oxidation for GLP2-2G-1-EX4-L5A (GLP2-L5A) after 7 months.
  • Example F The Stability of the Long-Acting GLP2R Agonists at Different pH Values
  • the stability of the peptides was measured across a range of pH values and temperatures.
  • GLP2-2G-1-EX4-L5A (GLP2-L5A) was 100% stable over 4 days.
  • GLP2-2G-10Nle-1K-EX4-K5 was also stable, with 95% of peptides remaining intact by 5 days, as depicted in FIG. 6 A .
  • GLP2-2G-10Nle-1K-EX4-K5 and GLP2-2G-1-EX4-L5A (GLP2-L5A) were less stable at a pH of 3.3 and a temperature of 37 degrees than they were at room temperature, as depicted in FIG. 6 B .
  • GLP2-2G-10Nle-1K-EX4-K5 and GLP2-2G-1-EX4-L5A underwent major hydrolysis at pH 3.4 ( ⁇ 18 Da and ⁇ 775 Da). Additionally, GLP2-2G-1-EX4-L5A (GLP2-L5A) was not soluble at pH 4.6.
  • GLP2-2G-10Nle-1K-EX4-K5 and GLP2-2G-1-EX4-L5A were 100% stable for 4 days at pH 7.5 at room temperature, as depicted in FIG. 6 C .
  • GLP2-2G-10Nle-1K-EX4-K5 underwent 1-% degradation and L5A underwent 1% degradation, as depicted in FIG. 6 D .
  • Both GLP2-2G-10Nle-1K-EX4-K5 and GLP2-2G-1-EX4-L5A (GLP2-L5A) were 100% stable for 4 days at pH 8.9 at room temperature, as depicted in FIG. 6 E .
  • FIG. 6 E At 37° C.
  • GLP2-2G-10Nle-1K-EX4-K5 underwent 1-% degradation
  • GLP2-2G-1-EX4-L5A underwent 1% degradation, as depicted in FIG. 6 F .
  • Example G The Stability of the Long-Acting GLP2R Agonists in Hepatocytes
  • the hepatocyte stability of the long-acting GLP2R agonists was measured over time.
  • GLP2-2G-1-EX4-L5A both the mouse and the MC values were slightly over 100% after 120 minutes, as depicted in FIG. 7 A .
  • the mouse values increased to slightly over 100%, the MC values decreased to approximately 60% after 120 minutes, as depicted in FIGS. 7 B- 7 C .
  • the biological half-lives (T 1 /2) and the intrinsic clearance (CLint) values were calculated for each peptide from the data, as listed in Table 11.
  • GLP2-2G-1-EX4-L5A had the highest half-life and the lowest CLint in both hepatocytes and in the liver.
  • GLP2-2G-10Nle-1-EX4-L5A had the lowest half-life and GLP2-2G-10Nle-1-EX4-L5A had the highest CLint values in both the hepatocytes and the liver.
  • mice Male C57BL/6 mice were dosed with GLP2-2G-1-EX4-L5A at 1.5 mg/kg in PBS (pH 7.5, clear solution) and the plasma concentration of agonists was tracked for 96 hours, as depicted in FIG. 8 .
  • Plasma concentration was analyzed using a LC-MS assay with a lower limit of quantification of 20 ng/mL. These values were also used to calculate other pharmacokinetic properties of this compound in mice, both for administration of the drug via intravenous injection and subcutaneous injection, as depicted in Table 12. A long in vivo half-life of around 8.4 hours was observed, similar to the 8-hour half-life of semaglutide in rodents.
  • GLP2-2G-1-EX4-L5A Male cyno monkeys were dosed with GLP2-2G-1-EX4-L5A at 1.0 mg/kg in PBS (pH 7.5, clear solution) and the plasma concentration of agonists tracked for 504 hours, as depicted in FIG. 9
  • Pharmacokinetic properties of GLP2-2G-1-EX4-L5A were analyzed for drug delivers via an IV and via a subcutaneous injection, as listed in Table 13. Plasma concentration was analyzed using a LC-MS assay with a lower limit of quantification of 10 ng/mL.
  • a long in vivo half-life of approximately 70 hours was observed, longer than the approximately 50-hour half-life of semaglutide in monkey. This long in vivo half-life indicated that potential translation into once-weekly human dosing may be possible.
  • mice Male C57BL/6 mice were dosed with GLP2-2G-10Nle-1-EX4-L5A at a concentration of 1.5 mg/kg in PBS (pH 7.5), either subcutaneously (SC) or intravenously (IV).
  • the plasma concentration of agonists was tracked for 96 hours after administration of the drug, as depicted in FIG. 10 .
  • Plasma concentration was analyzed using a LC-MS assay with a lower limit of quantification of 5 ng/mL.
  • Example L GLP2-2G-10Nle-1K-EX4-K5 Exhibited a Long In Vivo Half-Life in Mice
  • mice Male C57B3L/6 mice were dosed with GLP2-2G-10Nle-1K-EX4-K5 at a concentration of 1.5 mg/kg in PBS (pH 7.5), either subcutaneously (SC) or intravenously (IV).
  • the plasma concertation of agonists was tracked for 72 hours after administration of the drug, as depicted in FIG. 12 .
  • Plasma concentration was analyzed using a LC-MS assay with a lower limit of quantification of 5 ng/mL.
  • the pharmacokinetic properties of the drug in mice, including the half-life, was calculated from this data, and values are listed in Table 16. A long in vivo half-life of approximately 7 hours was observed for this drug in mice.
  • mice 13 week old female CD1 mice were divided into 5 treatment groups as listed: A (Vehicle PBS, SC, QD), B (GLP-C14, 0.05 mg/kg, BID), C (GLP2-2G-1-EX4-L5A, 0.1 mg/kg, QD), D (GLP2-2G-1-EX4-L5A, 1 mg/kg, QD), E (GLP2-2G-10Nle-1-EX4-L5A, 0.1 mg/kg, QD), and F (GLP2-2G-10Nle-1-EX4-L5A, 1 mg/kg, QD). 5 mice were in each group. The mice were administered the relevant dose subcutaneously either daily (QD) or twice a day (BID) using DPBS as the vehicle in a volume of 5 mL/kg and then monitored daily for bodyweight,
  • QD daily
  • BID twice a day
  • GI tract measurements were collected. These measurement included collecting terminal bleed; dissecting out the small intestine; and measuring the length and weight of the small intestine; recording the length and weight of the empty large intestine.
  • This example assessed the intestinotrophic effects of GLP2-2G-10Nle-1-Ex4-L5A in mice.
  • mice 7-8 week old male C57B6 mice were grouped into 6 experimental groups: A (Vehicle PBS, QD); B (teduglutide, 0.5 mg/kg, BID); C (GLP2-2G-10Nle-1K-EX4-K5, 0.03 mg/kg, QD); D (GLP2-2G-10Nle-1K-EX4-K5, 0.1 mg/kg, QD); E (GLP2-2G-10Nle-1K-EX4-K5, 0.3 mg/kg, QD); and F (GLP2-2G-10Nle-1K-EX4-K5, 1 mg/kg, QD).
  • Each treatment group contained 6 mice, except for group A, which contained 4.
  • mice were administered the treatment subcutaneously either once daily (QD) or twice daily (BID), using FPBS as a vehicle with a dosing volume of 5 mL/kg. Bodyweight was monitored daily and after 10 days of dosing, GI tract measurements were collected. These measurement included collecting terminal bleed; dissecting out the small intestine; measuring the length and weight of the small intestine; and recording the length and weight of the empty large intestine.
  • QD once daily
  • BID twice daily
  • mice that received high doses of GLP2-2G-10Nle-1-EX4-K5 showed significant increases in the length of the colon when compared to untreated controls (group A). All treatment groups showed a significant increase in colon weight when compared to untreated controls. However, the mice in groups E and F treated with the highest doses of GLP2-2G-10Nle-1-EX4-K5 showed the greatest increase.
  • Acute colitis was induced in mice by a single 5-day treatment course with 3% dextran sodium sulfate (DSS). Mice were divided into 4 treatments groups as listed: A (control mice that received no DSS), B (mice that received DSS and a subcutaneous injection of PBS), C (mice that received DSS and a 1 mg/kg subcutaneous treatment of GLP2-2G-1-EX4-L5), and D (mice that received DSS and a intraperitoneal treatment of 20 mg ⁇ kg of cyclosporin).
  • mice that received treatment for acute colitis did not have as great of a decrease in bodyweight when compared to untreated mice with induced colitis (group B). Additionally, mice in group C treated with GLP2-2G-1-EX4-L5A showed a significant increase in both colonic and small intestinal weight, as depicted in FIGS. 16 B- 16 C , compared to untreated mice with induced acute colitis (group B). Mice that were treated with GLP2-2G-1-EX4-L5A also showed significant increases in the length of both the colon and the small intestine when compared to untreated controls with induced acute colitis (figure not shown).
  • mice that received both DSS and L5A showed a similar crypt depth in the colon as mice that did not received DSS treatment, while mice that received only DSS had a significant reduction in crypt length, as depicted in FIG. 16 D .
  • the length of jejunum villi was greater in group C mice than in either group A or group B mice, as depicted in FIG. 16 E .
  • the group C mice did not show the villous distortion and abscesses exhibited by the group B mice.
  • mice 8 week old male C57BL/6 mice were divided into 7 treatments groups as listed: A (control mice that received no DSS), B (mice that received DSS and a subcutaneous injection of PBS), C (mice that received DSS and a 0.1 mg/kg subcutaneous treatment of GLP2-2G-10Nle-1K-EX4-K5), D (mice that received DSS and a 0.3 mg/kg subcutaneous treatment of GLP2-2G-10Nle-1K-EX4-K5, E (mice that received DSS and a 1 mg/kg subcutaneous treatment of GLP2-2G-10Nle-1K-EX4-K5), F (mice that received DSS and a 0.5 mg/kg subcutaneous treatment of teduglutide), and G (mice that received DSS and a IP treatment of 20 mg ⁇ kg of cyclosporin). Each group contained 6 mice, except for group A, which contained 4.
  • Acute colitis was induced in the mice by a single 5-day treatment course with 3% dextran sodium sulfate (DSS), as depicted in FIG. 17 A .
  • the animals were treated daily for 11 days with the appropriate dose per treatment group. The body weight was monitored daily. If animals lost more than 20% of their bodyweight, they were euthanized. On days 10-11, samples were collected for pharmacokinetic analysis at 0, 1, 3, 7 and 24 hours after the dose was administered. On day 11, animals were euthanized, and a necropsy was performed. The terminal bleed was collected into a heparinized collection tube and processed into plasma. The small intestine and colon were collected to measure weight and length. GI tissues were collected for histology.
  • mice in group G treated with cyclosporine showed a greater percent decrease in bodyweight during the DSS treatment than mice in any other treatment groups, but bodyweight increased after DSS treatment ended.
  • mice that received DSS and no treatment showed the greatest percent decrease in bodyweight after DSS treatment had ended when compared to all other treatment groups.
  • Mice that had been treated with either GLP2-2G-10Nle-1K-EX4-K5 (groups C-E) or with teduglutide (group F), along with mice that did not received DSS (group A) did not exhibit significant changes in bodyweight during this time.
  • GLP2-2G-10Nle-1K-EX4-K5 Treatment with GLP2-2G-10Nle-1K-EX4-K5 also affected the histological features of the intestines. All teduglutide and GLP2-2G-10Nle-1K-EX4-K5 treatment groups (groups C-F) showed a significant increase in villus height compared to untreated mice (groups A-B), as seen in FIG. 17 E . The lowest dose of GLP2-2G-10Nle-1K-EX4-K5, 0.1 mg/kg, administered once daily, showed comparable intestinotrophic effects to Teduglutide at 0.5 mg/kg, administered twice daily. Furthermore, Ki67 staining showed that there was no increased proliferation in any of the treatment groups, as depicted in FIG. 17 F . This showed that there was no evidence of abnormal proliferation associated with GLP2-2G-10Nle-1K-EX4-K5 treatment.
  • mice were divided into 9 treatment groups as listed: A (Non-DSS: Vehicle), B (DSS: Vehicle (PBS)), C (DSS: GLP2-2G-1-EX4-L5A, 0.03 mg/kg), D (DSS: GLP2-2G-1-EX4-L5A, 0.1 mg/kg), E (DSS: GLP2-2G-10Nle-1-EX4-L5A, 0.03 mg/kg), F (DSS: GLP2-2G-10Nle-1-EX4-L5A, 0.1 mg/kg), G (DSS: GLP2-2G-10Nle-1K-EX4-K5, 0.03 mg/kg), H (DSS: GLP2-2G-10Nle-1K-EX4-K5, 0.1 mg/kg), and I (DSS: Cyclosporine A, 20 mg/kg, IP).
  • mice Each group contain 6 C57BL/6 male mice aged 8 weeks. Mice were dosed with 3% DSS for 7 days and concurrently dosed with the appropriate treatment for 8 days to induce acute colitis. The animals were all dosed subcutaneously using a volume of 5 ml/kg and a vehicle of DPBS, with the except of group I, where the vehicle was olive oil. At days 6-7, pharmacokinetic samples were collected from groups C—H at 0, 1, 3, 7 and 24 hours after dosing. Measurements were taken at day 9. These measurement included collecting the terminal bleed; dissecting out the small intestine; measuring the length and weight of the small intestine; and recording the length and weight of the empty large intestine.
  • mice treated with either dose of GLP2-2G-10Nle-1K-Ex4-K5A had a greater overall bodyweight than those who received no treatment (group B). Furthermore, at a dose of 0.03 mg/kg, GLP2-2G-10Nle-1-Ex4-L5A and GLP2-2G-10Nle-1K-Ex4-K5 were more effective at protecting from bodyweight loss than GLP2-2G-1-EX4-L5A.
  • All 3 long acting-GLP-2 agonists increased colon length significantly in the acute DSS-induced colitis model at 0.1 mg/kg, as depicted in FIG. 18 D . Furthermore, there was a non-significant increasing trend on colon weight when comparing animals treated with long-acting GLP2 agonists to the untreated DSS animals, as depicted in FIG. 18 E . Furthermore, all 3 long-acting GLP2 agonists showed dose-related trophic effects on both the weight and length of the small intestine, as depicted in FIGS. 18 F- 18 G .
  • Treatment with GLP2R agonists also increased the size of the gall bladder, as depicted in FIG. 18 H . Additionally, the quantity of fecal occult blood was measured using a hemoccult II test, as depicted in FIG. 18 I .
  • Several treatment parameters such as both doses of 1L5A, decreased the hemoccult levels compared to the untreated DSS model mice.
  • the levels of the long-acting GLP2 agonists were measured over time. At doses of 0.03 mg/kg, the concentrations increased until 7 hours after administration but were still detectable at 24 hours after administration, as depicted in FIG. 18 J . At doses of 0.1 mg/kg, the concentrations increased until 7 hours after administration and were still detectable at 24 hours after administration, as depicted in FIG. 18 K .
  • GLP2-2G-1-EX4-L5A had the highest levels present, followed by GLP2-2G-10Nle-1-Ex4-L5A, then GLP2-2G-10Nle-1K-Ex4-K5.
  • the higher dose resulted in higher concentrations of the drug present at all tested time points, as depicted in FIGS. 18 L- 18 N .
  • Chronic DSS-induced colitis was induced in C57BL/6 mice (male, age 10-12 weeks) by 3 cycles of administration of 2.5% DSS in drinking water for 5 consecutive days, followed by 7 days of recovery. Animals were treated daily for 7 days during the last DSS-induction cycle. Treatment was administered either subcutaneously (S) or intraperitoneally (IP) either once daily (QD) or twice daily (BID).
  • S subcutaneously
  • IP intraperitoneally
  • QD once daily
  • BID twice daily
  • Bodyweight was monitored 3 times a week. Pharmacokinetic collection occurred 3 and 4 days prior to necropsy. At day 33, a necropsy was performed, and measurements were taken. These measurement included collecting terminal bleed; dissecting out the small intestine; measuring the length and weight of the small intestine; and recording the length and weight of the empty large intestine.
  • GLP2-2G-1-EX4-L5A was effective in treating weight loss in a mouse model of chronic colitis.
  • the mice which were treated with GLP2-2G-1-EX4-L5A or teduglutide did not show the same loss in percent of bodyweight or in overall bodyweight as seen in untreated mice (group B), as depicted in FIG. 19 A .
  • the protection from bodyweight loss was dose dependent, with the higher dose resulting in increased protection. Additionally, these effects were equivalent to teduglutide treatment at 0.3 mg/kg, QD.
  • GLP2-2G-1-EX4-L5A showed a dose-related restoration of colon length when compared to mice that received no treatment, as depicted in FIG. 19 B . Furthermore, when comparing the 0.3 mg/kg GLP2-2G-1-EX4-L5A treatment to the equivalent dose of teduglutide, the effects of GLP2-2G-1-EX4-L5A were less variable than the effects of teduglutide treatment. Colon weight was also affected by GLP2-2G-1-EX4-L5A and teduglutide treatment, as seen in FIG. 19 C . Mice treated with the low dose of GLP2-2G-1-EX4-L5A has a similar colon weight as those treated with teduglutide.
  • Chronic DSS-induced colitis was induced in C57BL/6 mice (male, age 10-12 weeks) by 3 cycles of administration of 2.5% DSS in drinking water for 5 consecutive days, followed by 7 days of recovery. Animals were treated daily for 7 days during the last DSS-induction cycle. Treatment was administered either subcutaneously (S) or intraperitoneally (IP) either once daily (QD) or twice daily (BID).
  • S subcutaneously
  • IP intraperitoneally
  • QD once daily
  • BID twice daily
  • Bodyweight was monitored 3 times a week. Pharmacokinetic collection occurred 3 and 4 days prior to necropsy. At day 33, a necropsy was performed, and measurements were taken. These measurement included collecting terminal bleed; dissecting out the small intestine; measuring the length and weight of the small intestine; and recording the length and weight of the empty large intestine.
  • GLP2-2G-10Nle-1-Ex4-L5A increased both colon length and weight in a chronic DSS-induced colitis model, as depicted in FIGS. 20 A- 20 B .
  • Colon length was significantly increased in animals treated with GLP2-2G-10Nle-1-Ex4-L5A at doses of 0.1 mg/kg and higher, as well as animals treated with teduglutide (groups D-G), when compared to untreated animals (group B).
  • Colon weight was increased in animals treated with GLP2-2G-10Nle-1-Ex4-L5A at doses of 0.3 mg/kg or higher, as well as in animals treated with teduglutide, compared to untreated animals.
  • GLP2-2G-10Nle-1-Ex4-L5A also significantly affected the small intestine weight and length.
  • Treatment with GLP2-2G-10Nle-1-Ex4-L5A at doses of 0.3 mg/kg or higher resulted in significant increases in small intestine weight compared with untreated mice (not depicted).
  • mice 5-week-old C57BL/6 mice were place on either a choline-deficient diet (CDAA, Dyets #518753) or an AA supplemented control diet (CSAA, Dyets #518754) for a total of 19 weeks.
  • Mice were divided into 3 treatment groups, with 8 mice per group, as listed: a CSAA control diet, treated with vehicle only; a CDAA diet treated with vehicle (MCT, PO; saline, SC); and a CDAA diet treated with 1 mg/kg subcutaneously of GLP2-2G-5-EX4-L5A. After 15 weeks, the mice were treated with either vehicle or compounds for 4 weeks. Body weight was monitored weekly during the diet induction phase and 3 times a week during the treatment phase. After 19 weeks, the animals were euthanized, and terminal blood and liver samples were harvested for serum panels, histology, and gene expression.
  • hepatic steatosis was analyzed by the percent of hepatocyte vacuolization determined by crisp, round, non-staining lipid vacuoles and assigned a grade based on the listed scale: 0 indicates less than 5%; 1 indicates 5-33%; 2 indicates 33-66%; and 3 indicates greater than 66%.
  • Treatment with GLP2-2G-5-EX4-L5A did not significantly affect the steatosis grade in the liver, as depicted in FIG. 21 D .
  • Lobular inflammation was analyzed by assessment of inflammatory foci for infiltrates of neutrophils, lymphocytes and macrophages.
  • Lobular inflammation was scored using the following scale: 0 indicates no foci; 1 indicates 2 foci/200 ⁇ field; 2 indicates 2-4 foci/200 ⁇ field; and 3 indicates more than 4 foci/200 ⁇ field.
  • Treatment with GLP-2-2G-5-L5A decreased the levels of lobular inflammation compared to untreated animals on the CDAA diet, as depicted in FIG. 21 E .
  • a weaning undernutrition model was used to assess the ability of GLP2-2G-10Nle-1K-EX4-K5 to treat environmental enteric dysfunction (EED). All dams were placed on an isocaloric Northeast Brazil (Regional Basic Diet—RBD), which was moderately deficient in protein, fat and minerals when their pups were 10 days old. At weaning (3 weeks of age), pups were placed on either a standard control diet (CD) or continued on RBD. At 4 weeks of age, weanlings were given drug or placebo (0.1 mg/kg formulated in PBS (vehicle)) once a day subcutaneously for 2-3 weeks. Bodyweight and food consumption were measured twice weekly.
  • mice Stool was collected at weaning, 6 weeks of age, and 8 weeks of age for calorimetry and microbiome. Oral FITC-dextran was used as a measurement of barrier function. At 6 weeks of age, mice were euthanized, and jejunal tissue was collected for morphology, immunohistochemistry, and for chamber analysis of transmucosal resistance and permeability. There were trends towards greater weight gain in both male and female RBD mice weaned to CD and treated with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5, as depicted in FIG. 22 A- 22 B . However, male and female mice weaned to RBD showed trends towards worsening weight when administered teduglutide or long-acting GLP2 agonist, as depicted in FIG. 22 C- 22 D .
  • CD males treated with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5 showed a significant increase in the small intestine wet body weight/body weight compared to untreated males, as depicted in FIG. 22 E .
  • CD females treated with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5 showed a significant increase in the small intestine wet body weight/body weight compared to untreated females, as depicted in FIG. 22 F .
  • GLP2-2G-10Nle-1K-EX4-K5 also resulted in a significant increase when compared to treatment with teduglutide.
  • RBD males treated with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5 showed a significant increase in the small intestine wet body weight/body weight compared to untreated males.
  • RBD females only animals treated with GLP2-2G-10Nle-1K-EX4-K5 showed a significant increase in the small intestine wet weight/bodyweight compared to that of untreated animals.
  • Treatment with GLP2-2G-10Nle-1K-EX4-K5 also had intestinotrophic effects on the animals.
  • CD males treated with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5 had significantly longer villus heights than untreated males.
  • CD females treated with GLP2-2G-10Nle-1K-EX4-K5 also had significantly longer villus lengths than untreated females.
  • the crypt depth of treated and untreated CD animals Males treated with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5 had longer crypt depths than untreated males.
  • the intestinal permeability was also measured in these mice, where the greater the FITC-dextran relative fluorescence, the greater the intestinal permeability.
  • CD males treated with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5 showed a trend towards decreased permeability in treated mice compared to untreated mice.
  • CD females treated with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5 showed a significant decreases in permeability when compared to untreated CD female mice.
  • Treatment with either teduglutide or GLP2-2G-10Nle-1K-EX4-K5 did not significantly affect the permeability of either RBD females or RBD males when compared to untreated mice.
  • CD and RBD mice had similar overall levels of permeability when treated with teduglutide.
  • Female might had slightly high levels of permeability when treated with GLP2-2G-10Nle-1K-EX4-K5 when compared to male mice on the same diet.

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US12583900B2 (en) 2019-12-04 2026-03-24 The Scripps Research Institute Peptide conjugates and methods of use
US12329823B2 (en) 2021-06-09 2025-06-17 The Scripps Research Institute Long-acting dual GIP/GLP-1 peptide conjugates and methods of use

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