WO2022257979A1 - Long-acting dual gip/glp-1 peptide conjugates and methods of use - Google Patents

Long-acting dual gip/glp-1 peptide conjugates and methods of use Download PDF

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WO2022257979A1
WO2022257979A1 PCT/CN2022/097662 CN2022097662W WO2022257979A1 WO 2022257979 A1 WO2022257979 A1 WO 2022257979A1 CN 2022097662 W CN2022097662 W CN 2022097662W WO 2022257979 A1 WO2022257979 A1 WO 2022257979A1
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peptide
peptide conjugate
amino acid
alkylene
seq
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English (en)
French (fr)
Inventor
Weijun Shen
Zaid AMSO
Peter G. Schultz
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Scripps Research Institute
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Scripps Research Institute
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Priority to EP22819576.4A priority Critical patent/EP4352088A4/en
Priority to AU2022289610A priority patent/AU2022289610A1/en
Priority to US18/568,244 priority patent/US20250320252A1/en
Priority to MX2023014771A priority patent/MX2023014771A/es
Priority to IL309067A priority patent/IL309067A/en
Priority to CA3221611A priority patent/CA3221611A1/en
Priority to JP2023576036A priority patent/JP2024522196A/ja
Priority to CN202280054598.5A priority patent/CN117794946A/zh
Application filed by Scripps Research Institute filed Critical Scripps Research Institute
Priority to KR1020247000049A priority patent/KR20240032010A/ko
Publication of WO2022257979A1 publication Critical patent/WO2022257979A1/en
Priority to US18/366,653 priority patent/US12329823B2/en
Anticipated expiration legal-status Critical
Priority to US19/169,978 priority patent/US20250325683A1/en
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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
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • 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
    • A61K47/54—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
    • 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
    • A61K47/595—Polyamides, e.g. nylon
    • 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
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • 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:
  • A is -N-
  • R is hydrogen or - (L) s -Y;
  • v 2-20;
  • R 1 and R 2 are taken together to form a C 1 -C 6 cycloalkyl or C 1 -C 6 heterocycloalkyl;
  • Y is hydrogen, C 1 -C 6 alkyl, -CO 2 H, -CO 2 (C 1 -C 6 alkyl) , -CO 2 NH 2 , -CO 2 N (alkyl) 2 , or -CO 2 NH (alkyl) ;
  • s is 0-20;
  • R a is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ; and
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 .
  • a peptide comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of any one of SEQ ID NOs: 1-61.
  • a peptide comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to any one of SEQ ID NOs: 1-61. Also provided herein is a peptide comprising a sequence at least 95%identical to SEQ ID NO. 6 (YAibEGT-FTSDY-SIYLD-KX1AAAib-EFVX2W-LIAGG-PSSGA-PPPS) .
  • a peptide comprising SEQ ID NO: 6 (YAibEGT-FTSDY-SIYLD-KX1AAAib-EFVX2W-LIAGG-PSSGA-PPPS) , or a peptide having 1 amino acid substitution, deletion, or insertion, or any combination thereof, as compared to SEQ ID NO: 6 (YAibEGT-FTSDY-SIYLD-KX1AAAib-EFVX2W-LIAGG-PSSGA-PPPS) .
  • the peptide comprises a sequence at least 98%identical to SEQ ID NO. 6. In some embodiments, the peptide comprises SEQ ID NO. 6. In some embodiments, the peptide comprises X1 and/or X2. In some embodiments, the peptide comprises X1, wherein X1 is a cysteine or lysine. In some embodiments, the peptide comprises X2, wherein X2 is a cysteine or lysine. In some embodiments, the peptide comprises X1 and X2, wherein X1 is cysteine and X2 is cysteine.
  • peptide conjugates comprising any peptide herein, and a staple.
  • peptide conjugates comprising a peptide at least 79%identical to SEQ ID NO: 6 (YAibEGT-FTSDY-SIYLD-KX1AAAib-EFVX2W-LIAGG-PSSGA-PPPS) , and a staple.
  • the peptide comprises X1 and/or X2 of SEQ ID NO: 6, and the staple is attached at the X1 and/or X2.
  • the peptide conjugate further comprising a fatty acid and/or half life extending moiety.
  • the staple is attached to the peptide at a first amino acid and a second amino acid; wherein the staple is of Formula (I) :
  • A is -N-
  • R is hydrogen or - (L) s -Y;
  • v 2-20;
  • R 1 and R 2 are taken together to form a C 1 -C 6 cycloalkyl or C 1 -C 6 heterocycloalkyl;
  • Y is hydrogen, C 1 -C 6 alkyl, -CO 2 H, -CO 2 (C 1 -C 6 alkyl) , -CO 2 NH 2 , -CO 2 N (alkyl) 2 , or -CO 2 NH (alkyl) ;
  • s is 0-20;
  • R a is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ; and
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 , and
  • the peptide comprises X1 and X2, and the first amino acid is X1 and the second amino acid is X2.
  • the first amino acid and the second amino acid are independently a sulfydryl containing amino acid.
  • the first amino acid and the second amino acid are independently selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid.
  • the first amino acid and second amino acids are cysteines.
  • the first amino acid and the second amino acid are independently an amine-containing amino acid.
  • the amine-containing amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine.
  • the first amino acid and the second amino acids are lysines. In some embodiments, 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. In some embodiments, the peptide modulates a GLP-1 receptor. In some embodiments, the peptide binds to a GLP-1 receptor. In some embodiments, the peptide modulates a GIP receptor. In some embodiments, the peptide binds to a GIP receptor. In some embodiments, the peptide is a GLP-1 receptor agonist. In some embodiments, the peptide is a GIP receptor agonist.
  • the peptide is a dual GLP-1 receptor and GIP receptor agonist. In some embodiments, the peptide is resistant to proteolysis by a gastrointestinal protease. In some embodiments, 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 binding affinity of the peptide conjugate is within about 5-20%of the binding affinity of an unmodified form of the peptide.
  • >A-R has the following structure:
  • the peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 3 and m is 15.
  • the peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n 2 and m is 15.
  • n 2 and m is 17.
  • the peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n 2 and m is 15.
  • n 2 and m is 17.
  • n 2 and m is 13.
  • the peptide conjugate comprises: L5A (S)
  • the peptide conjugate comprises: L5A
  • the peptide conjugate comprises: C20L5A
  • the peptide conjugate comprises: C16L5A
  • the peptide conjugate comprises: K4
  • the peptide conjugate comprises: K5
  • the peptide conjugate comprises: C20K5
  • composition comprising the peptide or peptide conjugate described herein and a pharmaceutically acceptable excipient.
  • Also provided 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 or peptide conjugate described herein.
  • the peptide or peptide conjugate may be administered about once every week, or about once every two weeks.
  • the disease or condition is diabetes or obesity.
  • the diabetes is Type 1 diabetes mellitus, Type 2 diabetes mellitus, gestational diabetes, neonatal diabetes, maturity onset diabetes of the young, or latent autoimmune diabetes in adults, or any combination thereof.
  • the disease or condition is non-alcoholic fatty liver disease (NAFLD) , nonalcoholic steatohepatitis (NASH) , or cardiovascular disease.
  • the disease or condition is short bowel syndrome (SBS) .
  • the disease or condition is inflammatory bowel disease (IBD) , inflammatory bowel syndrome (IBS) , or psoriasis.
  • the disease or condition is Crohn’s disease or ulcerative colitis.
  • the disease or condition is Alzheimer’s disease, Parkinson’s disease or Huntington’s disease.
  • the method further comprises administering to the subject one or more additional therapeutic agents.
  • the one or more additional therapeutic agents comprises an incretin hormone or a derivative thereof.
  • the incretin hormone or derivative thereof is selected from GLP-1, exendin-4, glucagon (GCG) , glucose-dependent insulinotropic polypeptide (GIP) , oxyntomodulin, and combinations thereof.
  • the peptide conjugate is administered about once every 7 days. In some embodiments, the peptide conjugate is administered about once every 14 days. In some embodiments, the peptide conjugate is administered about once a month. In some embodiments, the peptide conjugate is administered about once every two months. In some embodiments, the peptide conjugate is administered about once every three months.
  • FIG. 1A and FIG. 1B display example components of a peptide, such as amino acids.
  • FIGS. 2A-2B are graphs showing plasma glucose excursion during oral glucose tolerance tests (OGTT) in normal mice after 2 h (FIG. 2A) and 96 h (FIG. 2B) post injection.
  • C57B6 mice were s.c. injected with vehicle, L5A (mCMC759) , K5 (mCLZ715) , K4 (mCMD307) , or semaglutide (at 10 nmol/kg each) 2 h prior to the glucose challenge.
  • Statistics AUC and fasted glucose data were compared by one-way ANOVA followed by Dunnett’s multiple comparison tests vs. PBS-treated mice: ****P ⁇ . 0001; ***P ⁇ . 001.
  • FIG. 3 is a graph showing the pharmacokinetic profile of peptide mCMD307 (K4) after a single s.c. administration (1 mg kg-1) or i. v. administration (0.3 mg kg-1) in mice.
  • Blood samples were collected at the indicated time points and analyzed by in vitro GLP-1R activity assay. The assay was performed in triplicate. Pharmacokinetic analyses were determined by noncompartmental analysis with WinNonLin.
  • FIGS. 4A-4B show in vivo efficacy of mCMD307 (K4) in DIO mice treated for 7 days. Effects on body weight change (FIG. 4A, top) , crude body weight (FIG. 4A, middle) , cumulative food intake (FIG. 4A, bottom) , OGTT on day 7 (FIG. 4B, top and middle) , and fasted blood glucose on day 7 (FIG. 4B, bottom) .
  • C57BL/6 mice male, 37 weeks old
  • mCMD307 (K4) s.c. once daily; 10 nmol kg-1) or semaglutide (s.c.
  • FIGS. 5A-5E show in vivo efficacy of mCMD307 (2050-K4) in high-fat-diet-induced obesity (DIO) mice treated for 24 days. Effects on body weight and food intake change (FIG. 5A) , oral glucose tolerance test at day 21, fasted blood glucose prior to the OGTT (day 20) and fed glucose after the OGTT (day 21) (FIG. 5B) . Upon termination at day 24, measurement of liver enzyme ALT, AST, ALP levels and plasma cholesterol and triglyceride levels (FIG. 5C) and liver weight, liver triglyceride, liver/body weight ratio and fat weight (FIG.
  • FIG. 6A depicts the results of a GLP1 receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIG. 6B depicts the results of a GIP receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIG. 7A depicts the results of a GLP1 receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIG. 7B depicts the results of a GIP receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIG. 8A depicts the results of a GLP1 receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIG. 8B depicts the results of a GIP receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIG. 9A depicts the results of a GIP1 receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIG. 9B depicts the results of a GIP receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIG. 10 depicts the results of a GIP1 receptor activation reporter assay comparing the activity of semaglutide with the activities of various peptide conjugates.
  • FIGS. 11A-11B show the plasma concentration in mice versus time for peptide mCMV266 (FIG. 11A) and mCMV268 (FIG. 11B) administered via IV and SC.
  • FIG. 12 demonstrate extended PD effects of mCMV266 and mCMV268 peptide conjugates on fed glucose in C57B6 mice after a single SC dose of mCMV266 (3, 10 and 30 nmol/kg) and mCMV268 (3, 10 and 30 nmol/kg) .
  • FIG. 13 demonstrate the effects of mCMV266 and mCMV268 peptide conjugates on body weight and food consumption in wild-type C57B6 mice after a single SC dose of mCMV266 (3, 10 and 30 nmol/kg) and mCMV268 (3, 10 and 30 nmol/kg) .
  • FIG. 14 shows the plasma concentration in mice versus time for peptide mCMZ370 and mCMZ371 administered via IV and SC.
  • FIG. 15 demonstrates extended PD effects of mCMZ371 and mCMV268 peptide conjugates on fed glucose in C57B6 mice after a single SC dose of mCMZ371 (1, 3, 10 and 30 nmol/kg) and mCMV268 (3nmol/kg) . Results are compared to those testing Tirzepatide (kCMC760) after a single SC dose (10 nmol/kg) . Effects on body weight in the same animals was also graphed at each time point.
  • FIG. 16 shows plasma glucose excursion during oral glucose tolerance tests (OGTT) in normal mice after 12 h post injection.
  • C57B6 mice were single-dose SC injected with vehicle, Tirzepatide (kCMC760) (10 nmol/kg) , kCLD385 (10nmol/kg) , or mCMZ371 (1, 3, 10 or 30 nmol/kg) 12 hours prior to glucose challenge.
  • FIG. 16 also shows a graph of AUC calculations from this experiment.
  • FIG. 17 shows the plasma concentration in cynomolgus monkeys versus time for peptide mCMZ371 (CTR371) and mCMV268 administered via IV and SC.
  • FIG. 18 shows the plasma concentration in dogs versus time for peptide mCMZ371 (CTR371) and mCMV268.
  • CTR371 was administered via IV and SC.
  • mCMV268 was administered via IV and PO.
  • G protein-coupled receptors are membrane-bound proteins that have seven transmembrane domains linked by three intracellular and three extracellular loops. Their ligand-binding sites are highly specialized so that each receptor responds only to a limited variety of chemicals which bind with high affinity. Examples of GPCR ligands are peptides, proteins, lipid-derived molecules, small organic compounds and ions. GPCRs have been of long-standing interest as pharmaceutical drug targets, as they are involved in a plethora of pathophysiological processes, including the regulation of neuronal excitability, metabolism, reproduction, hormonal homeostasis, and behavior. It is estimated that around 34%of all Food and Drug Administration (FDA) approved drugs target 108 members of the GPCR family.
  • FDA Food and Drug Administration
  • GPCRs are generally classified into multiple superfamilies.
  • Family B GPCRs or the so-called secretin receptor family, are a small but structurally and functionally diverse set of receptors. These proteins are vital to many physiological functions and serve as key drug targets for several human diseases such as type 2 diabetes mellitus (T2DM) , migraine, osteoporosis, depression, and anxiety.
  • T2DM type 2 diabetes mellitus
  • Members of this family include receptors for polypeptide hormones of 27–141 residues in length.
  • GLP-1 and GLP-2 glucagon-like peptides
  • GLP-2 glucose-dependent insulinotropic polypeptide
  • VIP vasoactive intestinal peptide
  • PACAP pituitary adenylate cyclase-activating polypeptide
  • GHRH growth hormone-releasing hormone
  • GLP-1 Glucagon-like peptide 1
  • GLP-1R cognate receptor
  • GLP-1 receptor agonists represent a unique approach to the treatment of diabetes, with benefits beyond glucose control, including favorable effects on body weight, blood pressure, cholesterol levels, and beta-cell function.
  • Two short-acting (exenatide and liraglutide; once-or twice-daily administration) and three long-acting (albiglutide, dulaglutide, and exenatide LAR; weekly administration) GLP-1RAs are currently approved in the United States.
  • exenatide a GLP-1 analog originally isolated from the saliva of the Gila monster, has a half-life of 30 min after i. v. administration and a half-life of 2–3 h after s.c. administration in humans.
  • GLP-1RAs mimic the effects of the naturally occurring incretin hormone GLP-1 by activating GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release in a glucose-dependent manner-with a consequently low risk of hypoglycemia.
  • the effects of these GLP-1RAs on GLP-1 receptors in the CNS and the gastrointestinal tract also lead to reduced appetite and delayed glucose absorption, with concomitant weight loss. Given their limited oral bioavailability, these GLP-1RAs are currently given as an s.c. injection.
  • GLP-1RAs connected to a fatty-acid derived side-chain staple to increase half-life.
  • Incretin-based peptides are effective therapeutics for treating type 2 diabetes mellitus (T2DM) .
  • Oxyntomodulin (OXM) a dual agonist of GLP-1R and GCGR, has shown superior weight loss and glucose lowering effects, compared to single GLP-1R agonists.
  • OXM Oxyntomodulin
  • GLP-1R and GCGR dual agonists having increased plasma stability and higher potency in activating both GLP-1R and GCGR.
  • GIP is also characterized as an incretin that stimulates insulin secretion in a glucose-dependent manner.
  • a GIP and GLP-1 receptor dual agonist has been shown to reduce fasting serum glucose compared to placebo and to reduce body weight.
  • This dual agonist, LY3298176 is administered once-weekly subcutaneously.
  • GIPR and GLP-1R dual agonists comprising a stapled feature to increase serum stability and half-life.
  • peptides and peptide conjugates comprising a therapeutic peptide stapled to a molecule, such as a half-life extending molecule.
  • the stapled peptides comprise incretin peptides or incretin peptide mimetics.
  • Incretin peptides generally bind to their cognate receptors in an ⁇ -helical conformation, therefore certain embodiments herein provide for modifications that stabilize the ⁇ -helix, which in some cases may increase binding affinity to their receptors.
  • proteolytic stability may also be enhanced in a helical rather than an extended conformation.
  • conjugated peptides having increased circulatory half-life and potency toward their cognate receptors.
  • described herein is a peptide engineering strategy used to generate stapled long-acting peptide analogs with comparable potency as native peptides and significantly enhanced pharmacokinetic properties.
  • peptides and peptide conjugates comprising a peptide that modulates the GLP-1 receptor and/or the GIP receptor.
  • the peptide modulates both the GLP-1 receptor and the GIP receptor.
  • a peptide that modulates the GLP-1 receptor is a GLP-1 receptor agonist.
  • a peptide that modulates the GIP receptor is a GIP 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 peptide to a receptor (e.g., GLP-1 and/or GIP receptor) .
  • 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 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 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 peptide.
  • the peptide may comprise one or more sulfhydryl containing amino acid residues.
  • the one or more sulfhydryl containing amino acid residues may be used for connecting a staple.
  • the one or more sulfhydryl containing amino acid residues may be used for connecting a HEM (half-life extending molecule) .
  • the one or more sulfhydryl containing amino acid residues may be naturally occurring in the peptide.
  • the one or more sulfhydryl containing amino acid residues may be inserted into the peptide.
  • the one or more sulfhydryl containing amino acid residues may replace one or more amino acid residues in the peptide. Methods for amino acid substitution and/or insertion are known in the art.
  • the peptide may comprise one or more amine containing residues.
  • Non-limiting examples of amine containing residues include lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine.
  • the one or more amine containing residues may be used for connecting a staple.
  • the one or more one or more amine containing residues may be used for connecting a HEM.
  • the one or more one or more amine containing residues may be naturally occurring in the peptide.
  • the one or more one or more amine containing residues may be inserted into the peptide.
  • the one or more one or more amine containing residues may replace one or more amino acid residues in the peptide.
  • the peptide may comprise at least a portion of a wild-type peptide comprising 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 peptide.
  • the one or more amino acid mutations may comprise deletion of one or more amino acid residues of the wild-type peptide.
  • the one or more amino acid mutations may comprise substitution of one or more amino acid residues of the wild-type peptide.
  • the one or more amino acid mutations may comprise substituting one or more amino acid residues of the wild-type 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 peptide with one or more D-amino acid residues.
  • the one or more amino acid residues of the wild-type peptide may comprise one or more alanines, methionines, arginines, serines, threonines, and tyrosines.
  • the peptide 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.
  • the peptide may be a modified peptide with a D-serine in place of L-serine. In some embodiments, the peptide may be a modified with an aminoisobutyric acid [Aib] in place of L- serine. In some embodiments, the peptide may be a modified peptide with a neuroleucine [Nle] in place of leucine (Leu) . In some embodiments, the peptide comprises aMeF (alpha-methyl Phe) . In some embodiments, the peptide comprises 4Pal (4-pyridyl-Ala) . In some embodiments, the peptide comprises aMeL (alpha-methyl Leu) . In some embodiments, the peptide comprises Orn (ornithine) . In some embodiments, the peptide comprises aMeY (alpha-methyl tyrosine) .
  • the peptide comprises one or more of the following amino acids: N-methyl-Phe, D-Phe, alpha-methyl-Phe, Phe (2-F) , Phe (3-F) , Phe (4-F) , 4-Pyridyl-Ala, Aib, N-methyl-Leu, D-Leu, alpha-methyl-Leu, beta-3-Leu, beta-3-Phe, beta-3-Asn, beta-3-Trp, D-Asn, D-Glu, D-Gln, D-Asp.
  • the peptide comprises an amino acid of FIGS. 1A-1B.
  • the peptide comprises a sequence of any one of SEQ ID NOs: 1-61. In some cases, the peptide comprises a sequence at least about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 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: 1-61. In some cases, the peptide comprises a sequence at least about 90%identical to any one of SEQ ID NOs: 1-61.
  • the peptide comprises a sequence at least about 95%identical to any one of SEQ ID NOs: 1-61. In some cases, the peptide comprises a sequence at least about 99%identical to any one of SEQ ID NOs: 1-61. In some cases, the peptide 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: 1-61.
  • Non-limiting examples of peptides are shown in Table 1.
  • X refers to any natural or unnatural amino acid. Lower case letters refer to D-amino acids (e.g., “s” is D-serine) .
  • an X comprises a sulfydryl containing amino acid.
  • an X comprises an amine-containing amino acid.
  • an X is Lys.
  • an X is a Cys.
  • a first X of the peptide is an amine-containing amino acid and a second X of the peptide is a sulfydryl containing amino acid.
  • a second X of the peptide is an amine-containing amino acid and a first X of the peptide is a sulfydryl containing amino acid.
  • a peptide is resistant to a GI protease.
  • a GI protease resistant peptide comprises SEQ ID NO: 7.
  • a GI protease resistant peptide comprises SEQ ID NO: 9.
  • a GI protease resistant peptide comprises SEQ ID NO: 6.
  • the peptide comprises SEQ ID NO: 6, and the first X is a cysteine and the second X is a cysteine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of any one of SEQ ID NOs: 1-61.
  • a peptide or peptide conjugate comprising the first 28 amino acids of any one of SEQ ID NOs: 1-61.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to any one of SEQ ID NOs: 1-61.
  • a peptide or peptide conjugate comprising the peptide comprises any one of SEQ ID NOs: 1-61.
  • each X of any one of SEQ ID NOS: 1-61 is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 1.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 1.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 1.
  • a peptide or peptide conjugate comprising SEQ ID NO: 1.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 2.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 2.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 2.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 3.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 3.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 3.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 4.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 4.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 4.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 5.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 5.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 5.
  • a peptide or peptide conjugate comprising SEQ ID NO: 5.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 6.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 6.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 6.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • the first X is a cysteine and the second X is a cysteine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 7.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 7.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 7.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • aa6 is alpha-methyl Phe, N-methyl Phe, D-Phe, beta3-Phe, alpha-methyl Phe, alpha-methyl Phe (2-F) , alpha-methyl Phe (3-F) , and alpha-methyl (4-F) , Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • aa10 is alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • aa16 is L-Orn, alpha-methyl Lys, N-methyl Lys, D-Lys, or beta3-Lys.
  • aa25 is alpha-methyl Trp, N-methyl Trp, D-Trp, beta3-Trp, alpha-methyl Tyr, or Aib.
  • aa33 is A or E.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 8.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 8.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 8.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 9.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 9.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 9.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • aa6 is alpha-methyl Phe, N-methyl Phe, D-Phe, beta3-Phe, alpha-methyl Phe (2-F) , alpha-methyl Phe (3-F) , and alpha-methyl (4-F) , Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • aa10 is alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , Phe (4-F) , or 4-pyridyl-Ala.
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Val, Ile, or Aib.
  • aa16 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Val, Ile, or Aib.
  • aa24 is alpha-methyl Asn, N-methyl Asn, beta3-Asn, Aib, D-Asn, D-Asp, D-Glu, or D-Gln.
  • aa25 is alpha-methyl Trp, N-methyl Trp, D-Trp, beta3-Trp, alpha-methyl Tyr, or Aib.
  • aa33 is A or E.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 10.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 10.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 10.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • aa2 is Gly, Val, Leu, Ile, or Aib.
  • aa20 is Gly, Val, Leu, Ile, or Aib.
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 11.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 11.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 11.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • aa2 is Gly, Val, Leu, Ile, or Aib.
  • aa20 is Gly, Val, Leu, Ile, or Aib.
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 12.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 12.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 12.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • aa2 is Gly, Val, Leu, Ile, or Aib.
  • aa20 is Gly, Val, Leu, Ile, or Aib.
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 13.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 13.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 13.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • aa2 is Gly, Val, Leu, Ile, or Aib.
  • aa20 is Gly, Val, Leu, Ile, or Aib.
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 14.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 14.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 14.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 15.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 15.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 15.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 16.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 16.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 16.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 17.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 17.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 17.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 18.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 18.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 18.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 19.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 19.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 19.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 20.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 20.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 20.
  • a peptide or peptide conjugate comprising SEQ ID NO: 20.
  • each X is independently selected from a sulfhydryl- containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 21.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 21.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 21.
  • a peptide or peptide conjugate comprising SEQ ID NO: 21.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 22.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 22.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 22.
  • a peptide or peptide conjugate comprising SEQ ID NO: 22.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 23.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 23.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 23.
  • a peptide or peptide conjugate comprising SEQ ID NO: 23.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 24.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 24.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 24.
  • a peptide or peptide conjugate comprising SEQ ID NO: 24.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 25.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 25.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 25.
  • a peptide or peptide conjugate comprising SEQ ID NO: 25.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 26.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 26.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 26.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 27.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 27.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 27.
  • a peptide or peptide conjugate comprising SEQ ID NO: 27.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 28.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 28.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 28.
  • a peptide or peptide conjugate comprising SEQ ID NO: 28.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 29.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 29.
  • a peptide or peptide conjugate comprising a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 29.
  • a peptide or peptide conjugate comprising SEQ ID NO: 29.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • an X is a cysteine.
  • an X is a lysine.
  • a peptide or peptide conjugate comprising a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 30.
  • a peptide or peptide conjugate comprising the first 28 amino acids of SEQ ID NO: 30.
  • a peptide or peptide conjugate comprising a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 30.
  • a peptide or peptide conjugate comprising SEQ ID NO: 30.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid. In ssome cases, an X is a cysteine. In some cases, an X is a lysine.
  • peptide conjugates comprising a staple.
  • the staple attached to the peptide is of Formula (I) :
  • A is an optionally substituted alkylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted -NR 3 -alkylene-NR 3 -, or -N-;
  • X 1 is attached to a first amino acid of the peptide, and X 2 is attached to a second amino acid of the peptide;
  • R is hydrogen or - (L) s -Y;
  • v 2-20;
  • R 1 and R 2 are taken together to form a C 1 -C 6 cycloalkyl or C 1 -C 6 heterocycloalkyl;
  • Y is hydrogen, C 1 -C 6 alkyl, -CO 2 H, -CO 2 (C 1 -C 6 alkyl) , -CO 2 NH 2 , -CO 2 N (alkyl) 2 , or -CO 2 NH (alkyl) ;
  • s is 0-20;
  • R a is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 .
  • the staple attached to the peptide is of Formula (I) :
  • A is -N-
  • X 1 is attached to a first amino acid of the peptide
  • X 2 is attached to a second amino acid of the peptide
  • X 1 and X 2 are identical;
  • R is hydrogen or - (L) s -Y;
  • v 2-20;
  • R 1 and R 2 are taken together to form a C 1 -C 6 cycloalkyl or C 1 -C 6 heterocycloalkyl;
  • Y is hydrogen, C 1 -C 6 alkyl, -CO 2 H, -CO 2 (C 1 -C 6 alkyl) , -CO 2 NH 2 , -CO 2 N (alkyl) 2 , or -CO 2 NH (alkyl) ;
  • s is 0-20;
  • R a is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ; and
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 .
  • A is optionally substituted alkylene.
  • A is optionally substituted arylene. In some embodiments, A is arylene optionally substituted with halogen, alkyl, or haloalkyl. In some embodiments, A is unsubstituted arylene.
  • A is -NR 3 -alkylene-NR 3 -. In some embodiments, A is -N-.
  • X 1 and X 2 are identical. In some embodiments, X 1 and X 2 are different.
  • 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. In some embodiments, r1 and r2 are each 2.
  • >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.
  • 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.
  • the staple is N-(2-aminoethyl)
  • the staple attached to the peptide is wherein L 8 is - (CR 1 R 2 ) v -and v is 10-20.
  • the staple attached to the peptide is wherein 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 wherein L 18 is - (CR 1 R 2 ) v -and v is 10-20.
  • the staple attached to the peptide is wherein L 20 is - (CR 1 R 2 ) v -and v is 10-20.
  • the staple attached to the peptide is:
  • cysteine the being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue and the 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 being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue and the being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • n is 1 and m is 6.
  • n is 1 and m is 7.
  • n is 1 and m is 8.
  • n is 1 and m is 9.
  • n is 1 and m is 10.
  • n is 1 and m is 11.
  • n is 1 and m is 12. In some embodiments, n is 1 and m is 13. In some embodiments, n is 1 and m is 14. In some embodiments, n is 1 and m is 15. In some embodiments, n is 1 and m is 16. In some embodiments, n is 1 and m is 17. In some embodiments, n is 1 and m is 18. In some embodiments, n is 1 and m is 19. In some embodiments, n is 1 and m is 20. In some embodiments, n is 2 and m is 6. In some embodiments, n is 2 and m is 7. In some embodiments, n is 2 and m is 8. In some embodiments, n is 2 and m is 9.
  • n is 2 and m is 10. In some embodiments, n is 2 and m is 11. In some embodiments, n is 2 and m is 12. In some embodiments, n is 2 and m is 13. In some embodiments, n is 2 and m is 14. In some embodiments, n is 2 and m is 15. In some embodiments, n is 2 and m is 16. In some embodiments, n is 2 and m is 17. In some embodiments, n is 2 and m is 18. In some embodiments, n is 2 and m is 19. In some embodiments, n is 2 and m is 20. In some embodiments, n is 3 and m is 6. In some embodiments, n is 3 and m is 7.
  • n is 3 and m is 8. In some embodiments, n is 3 and m is 9. In some embodiments, n is 3 and m is 10. In some embodiments, n is 3 and m is 11. In some embodiments, n is 3 and m is 12. In some embodiments, n is 3 and m is 13. In some embodiments, n is 3 and m is 14. In some embodiments, n is 3 and m is 15. In some embodiments, n is 3 and m is 16. In some embodiments, n is 3 and m is 17. In some embodiments, n is 3 and m is 18. In some embodiments, n is 3 and m is 19. In some embodiments, n is 3 and m is 20.
  • n is 4 and m is 6. In some embodiments, n is 4 and m is 7. In some embodiments, n is 4 and m is 8. In some embodiments, n is 4 and m is 9. In some embodiments, n is 4 and m is 10. In some embodiments, n is 4 and m is 11. In some embodiments, n is 4 and m is 12. In some embodiments, n is 4 and m is 13. In some embodiments, n is 4 and m is 14. In some embodiments, n is 4 and m is 15. In some embodiments, n is 4 and m is 16. In some embodiments, n is 4 and m is 17. In some embodiments, n is 4 and m is 18. In some embodiments, n is 4 and m is 19. In some embodiments, n is 4 and m is 20.
  • the staple attached to the peptide is:
  • n is 1-4 and m is 6-20; the being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue and the being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • n is 1 and m is 6.
  • n is 1 and m is 7.
  • n is 1 and m is 8.
  • n is 1 and m is 9.
  • n is 1 and m is 10.
  • n is 1 and m is 11.
  • n is 1 and m is 12. In some embodiments, n is 1 and m is 13. In some embodiments, n is 1 and m is 14. In some embodiments, n is 1 and m is 15. In some embodiments, n is 1 and m is 16. In some embodiments, n is 1 and m is 17. In some embodiments, n is 1 and m is 18. In some embodiments, n is 1 and m is 19. In some embodiments, n is 1 and m is 20. In some embodiments, n is 2 and m is 6. In some embodiments, n is 2 and m is 7. In some embodiments, n is 2 and m is 8. In some embodiments, n is 2 and m is 9.
  • n is 2 and m is 10. In some embodiments, n is 2 and m is 11. In some embodiments, n is 2 and m is 12. In some embodiments, n is 2 and m is 13. In some embodiments, n is 2 and m is 14. In some embodiments, n is 2 and m is 15. In some embodiments, n is 2 and m is 16. In some embodiments, n is 2 and m is 17. In some embodiments, n is 2 and m is 18. In some embodiments, n is 2 and m is 19. In some embodiments, n is 2 and m is 20. In some embodiments, n is 3 and m is 6. In some embodiments, n is 3 and m is 7.
  • n is 3 and m is 8. In some embodiments, n is 3 and m is 9. In some embodiments, n is 3 and m is 10. In some embodiments, n is 3 and m is 11. In some embodiments, n is 3 and m is 12. In some embodiments, n is 3 and m is 13. In some embodiments, n is 3 and m is 14. In some embodiments, n is 3 and m is 15. In some embodiments, n is 3 and m is 16. In some embodiments, n is 3 and m is 17. In some embodiments, n is 3 and m is 18. In some embodiments, n is 3 and m is 19. In some embodiments, n is 3 and m is 20.
  • n is 4 and m is 6. In some embodiments, n is 4 and m is 7. In some embodiments, n is 4 and m is 8. In some embodiments, n is 4 and m is 9. In some embodiments, n is 4 and m is 10. In some embodiments, n is 4 and m is 11. In some embodiments, n is 4 and m is 12. In some embodiments, n is 4 and m is 13. In some embodiments, n is 4 and m is 14. In some embodiments, n is 4 and m is 15. In some embodiments, n is 4 and m is 16. In some embodiments, n is 4 and m is 17. In some embodiments, n is 4 and m is 18. In some embodiments, n is 4 and m is 19. In some embodiments, n is 4 and m is 20.
  • the staple attached to the peptide is:
  • n is 1-4 and m is 6-20; the being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue and the being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • n is 1 and m is 6.
  • n is 1 and m is 7.
  • n is 1 and m is 8.
  • n is 1 and m is 9.
  • n is 1 and m is 10.
  • n is 1 and m is 11.
  • n is 1 and m is 12. In some embodiments, n is 1 and m is 13. In some embodiments, n is 1 and m is 14. In some embodiments, n is 1 and m is 15. In some embodiments, n is 1 and m is 16. In some embodiments, n is 1 and m is 17. In some embodiments, n is 1 and m is 18. In some embodiments, n is 1 and m is 19. In some embodiments, n is 1 and m is 20. In some embodiments, n is 2 and m is 6. In some embodiments, n is 2 and m is 7. In some embodiments, n is 2 and m is 8. In some embodiments, n is 2 and m is 9.
  • n is 2 and m is 10. In some embodiments, n is 2 and m is 11. In some embodiments, n is 2 and m is 12. In some embodiments, n is 2 and m is 13. In some embodiments, n is 2 and m is 14. In some embodiments, n is 2 and m is 15. In some embodiments, n is 2 and m is 16. In some embodiments, n is 2 and m is 17. In some embodiments, n is 2 and m is 18. In some embodiments, n is 2 and m is 19. In some embodiments, n is 2 and m is 20. In some embodiments, n is 3 and m is 6. In some embodiments, n is 3 and m is 7.
  • n is 3 and m is 8. In some embodiments, n is 3 and m is 9. In some embodiments, n is 3 and m is 10. In some embodiments, n is 3 and m is 11. In some embodiments, n is 3 and m is 12. In some embodiments, n is 3 and m is 13. In some embodiments, n is 3 and m is 14. In some embodiments, n is 3 and m is 15. In some embodiments, n is 3 and m is 16. In some embodiments, n is 3 and m is 17. In some embodiments, n is 3 and m is 18. In some embodiments, n is 3 and m is 19. In some embodiments, n is 3 and m is 20.
  • n is 4 and m is 6. In some embodiments, n is 4 and m is 7. In some embodiments, n is 4 and m is 8. In some embodiments, n is 4 and m is 9. In some embodiments, n is 4 and m is 10. In some embodiments, n is 4 and m is 11. In some embodiments, n is 4 and m is 12. In some embodiments, n is 4 and m is 13. In some embodiments, n is 4 and m is 14. In some embodiments, n is 4 and m is 15. In some embodiments, n is 4 and m is 16. In some embodiments, n is 4 and m is 17. In some embodiments, n is 4 and m is 18. In some embodiments, n is 4 and m is 19. In some embodiments, n is 4 and m is 20.
  • the staple attached to the peptide is:
  • n is 1-4 and m is 6-20; the being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue and the being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • n is 1 and m is 6.
  • n is 1 and m is 7.
  • n is 1 and m is 8.
  • n is 1 and m is 9.
  • n is 1 and m is 10.
  • n is 1 and m is 11.
  • n is 1 and m is 12. In some embodiments, n is 1 and m is 13. In some embodiments, n is 1 and m is 14. In some embodiments, n is 1 and m is 15. In some embodiments, n is 1 and m is 16. In some embodiments, n is 1 and m is 17. In some embodiments, n is 1 and m is 18. In some embodiments, n is 1 and m is 19. In some embodiments, n is 1 and m is 20. In some embodiments, n is 2 and m is 6. In some embodiments, n is 2 and m is 7. In some embodiments, n is 2 and m is 8. In some embodiments, n is 2 and m is 9.
  • n is 2 and m is 10. In some embodiments, n is 2 and m is 11. In some embodiments, n is 2 and m is 12. In some embodiments, n is 2 and m is 13. In some embodiments, n is 2 and m is 14. In some embodiments, n is 2 and m is 15. In some embodiments, n is 2 and m is 16. In some embodiments, n is 2 and m is 17. In some embodiments, n is 2 and m is 18. In some embodiments, n is 2 and m is 19. In some embodiments, n is 2 and m is 20. In some embodiments, n is 3 and m is 6. In some embodiments, n is 3 and m is 7.
  • n is 3 and m is 8. In some embodiments, n is 3 and m is 9. In some embodiments, n is 3 and m is 10. In some embodiments, n is 3 and m is 11. In some embodiments, n is 3 and m is 12. In some embodiments, n is 3 and m is 13. In some embodiments, n is 3 and m is 14. In some embodiments, n is 3 and m is 15. In some embodiments, n is 3 and m is 16. In some embodiments, n is 3 and m is 17. In some embodiments, n is 3 and m is 18. In some embodiments, n is 3 and m is 19. In some embodiments, n is 3 and m is 20.
  • n is 4 and m is 6. In some embodiments, n is 4 and m is 7. In some embodiments, n is 4 and m is 8. In some embodiments, n is 4 and m is 9. In some embodiments, n is 4 and m is 10. In some embodiments, n is 4 and m is 11. In some embodiments, n is 4 and m is 12. In some embodiments, n is 4 and m is 13. In some embodiments, n is 4 and m is 14. In some embodiments, n is 4 and m is 15. In some embodiments, n is 4 and m is 16. In some embodiments, n is 4 and m is 17. In some embodiments, n is 4 and m is 18. In some embodiments, n is 4 and m is 19. In some embodiments, n is 4 and m is 20.
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the staple attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the staple attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the staple attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the staple attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the staple attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide is:
  • the staple attached to the peptide comprises Linker L1, Linker L2, or Linker L3:
  • X independently comprises C14, C14 diacid, C16, C16 diacid, C18, C18 diacid, C20 or C20 diacid.
  • X comprises Propionic acid (CH3CH2COOH, C3: 0) .
  • X comprises Butyric acid (Butanoic acid, CH3 (CH2) 2COOH, C4: 0) .
  • X is Valeric acid (Pentanoic acid, CH3 (CH2) 3COOH, C5: 0) .
  • X comprises Caproic acid (Hexanoic acid, CH3 (CH2) 4COOH, C6: 0) .
  • X comprises Enanthic acid (Heptanoic acid, CH3 (CH2) 5COOH, C7: 00.
  • X comprises Caprylic acid (Octanoic acid, CH3 (CH2) 6COOH, C8: 0) .
  • X comprises Pelargonic acid (Nonanoic acid, CH3 (CH2) 7COOH, C9: 0) .
  • X comprises Capric acid (Decanoic acid, CH3 (CH2) 8COOH, C10: 0) .
  • X comprises Undecylic acid (Undecanoic acid, CH3 (CH2) 9COOH, C11: 0) .
  • X comprises Lauric acid (Dodecanoic acid, CH3 (CH2) 10COOH, C12: 0) .
  • X comprises Tridecylic acid (Tridecanoic acid, CH3 (CH2) 11COOH, C13: 0) .
  • X comprises Myristic acid (Tetradecanoic acid, CH3 (CH2) 12COOH, C14: 0) .
  • X comprises Pentadecylic acid (Pentadecanoic acid, CH3 (CH2) 13COOH, C15: 0) .
  • X comprises Palmitic acid (Hexadecanoic acid, CH3 (CH2) 14COOH, C16: 0) .
  • X comprises Margaric acid (Heptadecanoic acid, CH3 (CH2) 15COOH, C17: 0) .
  • X comprises Stearic acid (Octadecanoic acid, CH3 (CH2) 16COOH, C18: 0) .
  • X comprises Nonadecylic acid (Nonadecanoic acid, CH3 (CH2) 17COOH, C19: 0) .
  • X comprises Arachidic acid (Eicosanoic acid, CH3 (CH2) 18COOH, C20: 0) .
  • X comprises Heneicosylic acid (Heneicosanoic acid, CH3 (CH2) 19COOH, C21: 0) .
  • X comprises Behenic acid (Docosanoic acid, CH3 (CH2) 20COOH, C22: 0) .
  • X comprises Tricosylic acid (Tricosanoic acid, CH3 (CH2) 21COOH, C23: 0) .
  • X comprises Lignoceric acid (Tetracosanoic acid, CH3 (CH2) 22COOH, C24: 0) . In some embodiments, X comprises Pentacosylic acid (Pentacosanoic acid, CH3 (CH2) 23COOH, C25: 0) .
  • peptide conjugates comprising a HEM.
  • the HEM attached to the peptide is of Formula (II) :
  • v 2-20;
  • R 1 and R 2 are taken together to form a C 1 -C 6 cycloalkyl or C 1 -C 6 heterocycloalkyl;
  • Y is hydrogen, C 1 -C 6 alkyl, -CO 2 H, -CO 2 (C 1 -C 6 alkyl) , -CO 2 NH 2 , -CO 2 N (alkyl) 2 , or -CO 2 NH (alkyl) ;
  • s is 0-20;
  • R a is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 .
  • X 3 is a bond
  • each R 3 is independently hydrogen or C 1 -C 6 alkyl. In some embodiments, each R 3 is hydrogen.
  • 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.
  • 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.
  • the HEM attached to the peptide is:
  • cysteine the being part of a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, or 2-amino-6-mercaptohexanoic acid residue, and the being part of a lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue.
  • the HEM attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the HEM attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the HEM attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the HEM attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the HEM attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • the HEM attached to the peptide is:
  • amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide.
  • peptide conjugates comprising: a peptide and a staple attached to the peptide at a first amino acid and a second amino acid.
  • the peptide conjugates comprise (a) a peptide that modulates a GIP-1R receptor; and (b) a staple attached to the peptide at a first amino acid and a second amino acid.
  • the peptide conjugates comprise (a) a peptide that binds to a GLP-1 receptor; and (b) a staple attached to the peptide at a first amino acid and a second amino acid.
  • the peptide conjugates comprise (a) a peptide that modulates a GIP receptor; and (b) a staple attached to the peptide at a first amino acid and a second amino acid.
  • the peptide conjugates comprise (a) a peptide that binds a GIP receptor; and (b) a staple attached to the peptide at a first amino acid and a second amino acid.
  • Non-limiting examples of 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 connected by a staple are about or at least about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 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 is at the 14 position and the second amino acid is at the 21 position in the peptide.
  • the first amino acid is at the 17 position and the second amino acid is at the 24 position in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i + 4 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i + 5 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i + 6 in the peptide.
  • 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 + 8 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i + 9 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i + 10 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 + 12 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i + 13 in the peptide.
  • the first amino acid has a position i in the peptide and the second amino acid has a position i + 14 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.
  • the first amino acid and the second amino acid are independently selected from the group consisting of an amine-containing amino acid and a sulfhydryl-containing amino acid.
  • the first amino acid and second amino acid is independently selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid. In some embodiments, the first amino acid and second amino acid are cysteines.
  • the first amino acid and second amino acid is independently selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine.
  • the first amino acid and second amino acid are lysines.
  • the first amino acid and second amino acid are ornithines.
  • the peptide conjugate further comprises a half-life extending molecule attached to a sulfhydryl containing amino acid or an amine-containing amino acid residue in the peptide.
  • the amine-containing amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid, and homolysine.
  • the amine-containing amino acid is lysine.
  • the sulfhydryl-containing amino acid is selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid.
  • the sulfhydryl-containing amino acid is cysteine.
  • the peptide comprises a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of any one of SEQ ID NOs: 1-61.
  • the peptide comprises a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to any one of SEQ ID NOs: 1-61.
  • the peptide comprises a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 6.
  • peptide conjugates comprising: a peptide and a staple.
  • the staple and/or peptide may comprise a half-life extending moiety (HEM) .
  • the peptide conjugates comprise (a) a peptide that modulates a GIP-1R receptor; and (b) a half-life extending moiety (HEM) attached to the peptide at a first amino acid.
  • HEM half-life extending moiety
  • the peptide conjugates comprise (a) a peptide that binds to a GLP-1 receptor; and (b) a half-life extending moiety (HEM) attached to the peptide at a first amino acid.
  • HEM half-life extending moiety
  • the peptide conjugates comprise (a) a peptide that modulates a GIP receptor; and (b) a half-life extending moiety (HEM) attached to the peptide at a first amino acid.
  • HEM half-life extending moiety
  • the peptide conjugates comprise (a) a peptide that binds a GIP receptor; and (b) a half-life extending moiety (HEM) attached to the peptide at a first amino acid.
  • HEM half-life extending moiety
  • Non-limiting examples of 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 first amino acid is selected from the group consisting of an amine-containing amino acid and a sulfhydryl-containing amino acid.
  • the first amino acid is selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid.
  • the first amino acid is cysteine.
  • the first amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine.
  • the first amino acid is lysine.
  • the first amino acid is ornithine.
  • the peptide conjugate further comprises a second half-life extending moiety attached to a sulfhydryl containing amino acid or an amine-containing amino acid residue in the peptide.
  • the amine-containing amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid, and homolysine.
  • the amine-containing amino acid is lysine.
  • the sulfhydryl-containing amino acid is selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid.
  • the sulfhydryl-containing amino acid is cysteine.
  • the peptide may modulate and/or bind to: a GLP-1 receptor, a GIP receptor, or a GLP-1 receptor and GIP receptor.
  • the peptide comprises two amino acids connected by a staple.
  • Non-limiting examples of amino acids for use in conjugation include cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, or other sulfhydryl containing amino acids.
  • the two amino acids may be 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.
  • the first amino acid and the second amino acid are independently selected from sulfhydryl-containing amino acids.
  • the first amino acid and second amino acid is independently selected from cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, and 2-amino-6-mercaptohexanoic acid. In some embodiments, the first amino acid and second amino acid are cysteines.
  • a peptide herein is conjugated to a structure of Table 2.
  • Each of L5A, C20L5A, C16L5A, K4, K5, and C20K5 is connected to an amino acid of the peptide.
  • the amino acid is a cysteine, homocysteine, 2-amino-5-mercaptopentanoic acid, 2-amino-6-mercaptohexanoic acid, lysine, ornithine, diaminobutyric acid, diaminopropionic acid, or homolysine residue of the peptide
  • the peptide comprises a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of any one of SEQ ID NOs: 1-61.
  • the peptide comprises a sequence about or at least about 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to any one of SEQ ID NOs: 1-61.
  • a peptide conjugate comprises:
  • a staple comprising Linker L1 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L1 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L1 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L1 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L2 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L2 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L2 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L2 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L3 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L3 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L3 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • a staple comprising Linker L3 attached to the peptide at a first amino acid and a second amino acid.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 2 and m is 15, n is 2 and m is 17, or n is 2 and m is 13.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 3 and m is 15.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 2 and m is 15, or n is 2 and m is 17.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 2 and m is 15, n is 2 and m is 17, or n is 2 and m is 13.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 3 and m is 15.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 2 and m is 15, or n is 2 and m is 17.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 2 and m is 15, n is 2 and m is 17, or n is 2 and m is 13.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 3 and m is 15.
  • a peptide conjugate comprises:
  • n is 1-4 and m is 6-20.
  • n is 2 and m is 15, or n is 2 and m is 17.
  • a peptide conjugate comprises:
  • a) a peptide comprising the peptide comprises any one of SEQ ID NOs: 1-61;
  • n is 1-4 and m is 6-20.
  • n is 2 and m is 15, n is 2 and m is 17, or n is 2 and m is 13.
  • a peptide conjugate comprises:
  • a) a peptide comprising the peptide comprises any one of SEQ ID NOs: 1-61;
  • n is 1-4 and m is 6-20.
  • n is 3 and m is 15.
  • a peptide conjugate comprises:
  • a) a peptide comprising the peptide comprises any one of SEQ ID NOs: 1-61;
  • n is 1-4 and m is 6-20.
  • n is 2 and m is 15, or n is 2 and m is 17.
  • a peptide conjugate comprises:
  • L5A L5A (S) .
  • a peptide conjugate comprises:
  • L5A L5A (S) .
  • a peptide conjugate comprises:
  • L5A L5A (S) .
  • a peptide conjugate comprises:
  • L5A L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising C16L5A attached to the peptide at a first amino acid and a second amino acid.
  • the C16L5A is C16L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising C16L5A attached to the peptide at a first amino acid and a second amino acid.
  • the C16L5A is C16L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising C16L5A attached to the peptide at a first amino acid and a second amino acid.
  • the C16L5A is C16L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising C16L5A attached to the peptide at a first amino acid and a second amino acid.
  • the C16L5A is C16L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising C20L5A attached to the peptide at a first amino acid and a second amino acid.
  • the C20L5A is C20L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising C20L5A attached to the peptide at a first amino acid and a second amino acid.
  • the C20L5A is C20L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising C20L5A attached to the peptide at a first amino acid and a second amino acid.
  • the C20L5A is C20L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising C20L5A attached to the peptide at a first amino acid and a second amino acid.
  • the C20L5A is C20L5A (S) .
  • a peptide conjugate comprises:
  • a staple comprising K4 attached to the peptide at a first amino acid and a second amino acid.
  • the K4 is K4 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising K4 attached to the peptide at a first amino acid and a second amino acid.
  • the K4 is K4 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising K4 attached to the peptide at a first amino acid and a second amino acid.
  • the K4 is K4 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising K4 attached to the peptide at a first amino acid and a second amino acid.
  • the K4 is K4 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising K5 attached to the peptide at a first amino acid and a second amino acid.
  • the K5 is K5 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising K5 attached to the peptide at a first amino acid and a second amino acid.
  • the K5 is K5 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising K5 attached to the peptide at a first amino acid and a second amino acid.
  • the K5 is K5 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising K5 attached to the peptide at a first amino acid and a second amino acid.
  • the K5 is K5 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising C20K5 attached to the peptide at a first amino acid and a second amino acid.
  • the C20K5 is C20K5 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising C20K5attached to the peptide at a first amino acid and a second amino acid.
  • the C20K5 is C20K5 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising C20K5 attached to the peptide at a first amino acid and a second amino acid.
  • the C20K5 is C20K5 (NH) .
  • a peptide conjugate comprises:
  • a staple comprising C20K5 attached to the peptide at a first amino acid and a second amino acid.
  • the C20K5 is C20K5 (NH) .
  • a peptide conjugate described herein is as shown in Table 3.
  • a peptide conjugate comprising:
  • A is -N-
  • R is hydrogen or - (L) s -Y;
  • v 2-20;
  • R 1 and R 2 are taken together to form a C 1 -C 6 cycloalkyl or C 1 -C 6 heterocycloalkyl;
  • Y is hydrogen, C 1 -C 6 alkyl, -CO 2 H, -CO 2 (C 1 -C 6 alkyl) , -CO 2 NH 2 , -CO 2 N (alkyl) 2 , or -CO 2 NH (alkyl) ;
  • s is 0-20;
  • R a is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R b is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ; and
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, -OH, -OMe, or -NH 2 ; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 ;
  • R c and R d together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, -OH, -OMe, or -NH 2 .
  • amine-containing amino acid is selected from lysine, ornithine, diaminobutyric acid, diaminopropionic acid and homolysine.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of any one of SEQ ID NOs: 1-61.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to any one of SEQ ID NOs: 1-61.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 1.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 1.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 2.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 3.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 3.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 4.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 4.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 5.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 5.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 6.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 6.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 7.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 7.
  • aa6 is alpha-methyl Phe, N-methyl Phe, D-Phe, beta3-Phe, alpha-methyl Phe, alpha-methyl Phe (2-F) , alpha-methyl Phe (3-F) , and alpha-methyl (4-F) , Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • aa16 is L-Orn, alpha-methyl Lys, N-methyl Lys, D-Lys, or beta3-Lys.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 8.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 8.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 9.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 9.
  • aa6 is alpha-methyl Phe, N-methyl Phe, D-Phe, beta3-Phe, alpha-methyl Phe (2-F) , alpha-methyl Phe (3-F) , and alpha-methyl (4-F) , Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • aa10 is alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , Phe (4-F) , or 4-pyridyl-Ala.
  • aa24 is alpha-methyl Asn, N-methyl Asn, beta3-Asn, Aib, D-Asn, D-Asp, D-Glu, or D-Gln
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 10.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 10.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • 111 The peptide conjugate of any one of embodiments 104-110, wherein aa2 is Gly, Val, Leu, Ile, or Aib.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 11.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 11.
  • 121 The peptide conjugate of any one of embodiments 114-120, wherein aa2 is Gly, Val, Leu, Ile, or Aib.
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 12.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 12.
  • aa2 is Gly, Val, Leu, Ile, or Aib.
  • 133 The peptide conjugate of any one of embodiments 124-132, wherein aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 13.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 13.
  • aa13 is alpha-methyl Leu, N-methyl Leu, D-Leu, beta3-Leu, Leu, Val, Ile, Aib, alpha-methyl Tyr, N-methyl Tyr, D-Tyr, beta3-Tyr, 4-Pyr-Ala, Phe (2-F) , Phe (3-F) , or Phe (4-F) .
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 14.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 14.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 15.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 15.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 16.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 16.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 17.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 17.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 18.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 18.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 19.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 19.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 20.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 20.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 21.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 21.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 22.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 22.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 23.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 23.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 24.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 24.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 25.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 25.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 26.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 26.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 27.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 27.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 28.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 28.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 29.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 29.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 30.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to SEQ ID NO: 30.
  • each X is independently selected from a sulfhydryl-containing amino acid and an amine-containing amino acid.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of any one of SEQ ID NOS: 31-61.
  • peptide conjugate of any one of embodiments 1-20 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to any one of SEQ ID NOS: 31-61.
  • peptide conjugate of any one of embodiments 1-277, wherein the peptide conjugate comprises: wherein n is 1-4 and m is 6-20.
  • a peptide conjugate comprising mCMD307 (Table 3) .
  • a peptide conjugate comprising: mCMV266 (Table 3) .
  • a peptide conjugate comprising: mCMV268 (Table 3) .
  • a peptide conjugate comprising any molecule of Table 3.
  • a peptide conjugate comprising:
  • peptide conjugate of embodiment 312 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of any one of SEQ ID NOs: 1-61.
  • peptide conjugate of embodiment 312 wherein the peptide comprises a sequence about or at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%identical to the first 28 amino acids of SEQ ID NO: 1.

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