Table 5.
Multiagonists based on proglucagon-derived peptides in development.
| Peptide Name | AA Sequence | Target Receptors | Development Stage | Reference |
|---|---|---|---|---|
| Dual Agonists | ||||
| Cotadutide | HSQGTFTSDK-(Palmitoyl-E)SEYLDSERARDFVAWLEAGG | GLP-1R/GCGR | Phase II-T2DM, NASH/NAFLD (AstraZeneca) | (291–292, 293) |
| Efinopegdutide | Structure N/A | GLP-1R/GCGR | Phase II-NASH/NAFLD (Merck & Co) | (294–295) |
| Tirzepatide | Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*(C20 diacid γ-E)AFVQWLIAGGPSSGAPPPS | GLP-1R/GIPR | Phase III-T2DM, Phase II-NASH (Eli Lilly) | (296–297) |
| NN9389 | Structure N/A (GIP/Semaglutide Preparation) | GLP-1R/GIPR | Phase I-T2DM (Novo Nordisk) | (298) |
| CT-868 | Structure N/A | GLP-1R/GIPR | Phase I-T2DM (Carmot Therapeutics) | (298) |
| TAK-094 | Structure N/A | GLP-1R/GIPR | Phase I-T2DM (Takeda Pharmaceuticals) | (298) |
| (pGlu-Gln)-CCK-8/exendin-4 | pEQDY-(SO3H)-MGWMDF-(AEEAc-AEEAc)-HGEGTFTSDLSKQMEEEAVRLFIEWLKN | GLP-1R/CCK1R | Preclinical | (299) |
| C2816 | HGEGTFTSDLSKQMEEEAVRLFIEWLKN-[PEG4]-Nle-GWK(Tac)D-NmeF | GLP-1R/CCK1R | Preclinical (MedImmune/Astrazeneca) | (300) |
| GUB06-046 | HXEGTFTSDLSRLLEGAALQRFIQWLV | GLP-1R/SCTR | Preclinical (Gubra) | (301) |
| EP45 | HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSRHYLNLVTRQRY | GLP-1R/NPY2R | Preclinical | (302) |
| Exendin‐4/xenin‐8‐Gln | HGEGTFTSDLSKQMEEEAVRLFIEWLKN‐(AEEAc‐AEEAc)‐HPQQPWIL | GLP-1/NTSR1 | Preclinical | (303) |
| Triple Agonists | ||||
| YAG-glucagon | Y[DA]QGTFTSDYSIYLDSNVAQDFVQWLIGG | GLP-1/GIPR/GCGR | Preclinical | (304) |
| Exendin‐4/gastrin/xenin‐8‐Gln | HGEGTFTSDLSKQMEEEAVRLFIEWLKN‐(AEEAc‐AEEAc)‐YGWLDF ‐(AEEAc‐AEEAc)‐HPQQPWIL | GLP-1/CCK2R/NTSR1 | Preclinical | (305) |
| Exendin‐4(Lys27γ‐Glu‐PAL)/gastrin/xenin‐8‐Gln | HGEGTFTSDLSKQMEEEAVRLFIEWLK(γ‐E‐PAL)N‐(AEEAc‐AEEAc)‐YGWLDF ‐(AEEAc‐AEEAc)‐HPQQPWIL | GLP-1/CCK2R/NTSR1 | Preclinical | (306) |
| LY3437943 | Structure N/A | GLP-1/GIPR/GCGR | Phase I (Eli Lilly) | (269) |
| HM15211 | Structure N/A | GLP-1/GIPR/GCGR | Phase II (Hanmi Pharmaceuticals) | (307–308) |
| TA | HXQGTFTSDK*(γE-C16)SKYLDERAAQDFVQWLLDGGPSSGAPPPS | GLP-1/GIPR/GCGR | Preclinical | (309, 310) |
Amino acid sequences are provided in their single-letter abbreviation format. The receptor targets for each molecule, as well as current stage of development and holding companies (in brackets, where available) are provided for each. A “D” prefix before a residue indicates inclusion of the enantiomer for the naturally-occurring L form of the residue. “PAL” indicates the addition of a palmitic fatty acid chain, “PEG” indicates a polyethylene glycol linker. “Aib”, “Nle” and “NmeF” indicate the addition of an unnatural 2-aminoisobutyric acid, norleucine or N-methyl phenylalanine residues. “pE” indicates pyroglutamine. “K(Tac)” indicates inclusion of a side-chain substituted (o-tolyamino)carbonyl lysine residue. “(AEEAc‐AEEAc)” indicates a commonly employed linker molecule between peptide regions. “γE-PAL” represents a fatty acid attachment.