GLP-1R is the hottest target in peptide therapeutics. Semaglutide (Ozempic/Wegovy), liraglutide (Victoza/Saxenda), dulaglutide (Trulicity), and tirzepatide (Mounjaro) are multi-billion-dollar drugs acting on this receptor.
Next-gen candidates include retatrutide (triple agonist: GLP-1R/GIPR/GCGR), CagriSema (semaglutide + cagrilintide combo, PDUFA ~Oct 2026), and oral formulations. The key challenge: muscle loss under GLP-1 therapy drives interest in myostatin inhibition as a combination strategy.
GLP-1R is the class B GPCR that mediates GLP-1's incretin effects - glucose-dependent insulin secretion, glucagon suppression, gastric emptying delay, and hypothalamic satiety signaling. It is the most commercially successful peptide drug target in history: over 10 approved GLP-1R agonists generated >$20 billion in annual revenue by 2024, with semaglutide (Ozempic/Wegovy) dominating weight loss medicine. GLP-1R activation also provides cardioprotection, beta-cell preservation, neuroprotection, and renal benefits. Every scaffold for diabetes, obesity, neurodegeneration, or cardiometabolic disease that involves incretin biology is forked from this card.
GLP-1R (chromosome 6p21.2, 463 aa) adopts the canonical class B GPCR architecture: ~130-aa N-terminal ECD stabilized by three disulfide bonds (initial ligand capture), seven TM helices (activation core), and an intracellular C-tail with GRK phosphorylation sites. GLP-1 (30 aa: GLP-1(7-36)amide or GLP-1(7-37)) is secreted by L cells in the distal intestine; plasma half-life <2 minutes due to DPP-4 cleavage at position 2 (His7-Ala8 bond). Two-domain binding: GLP-1 C-terminus engages ECD, N-terminus inserts into the TM bundle to drive activation. Outward TM6 displacement opens the Gs docking crevice → adenylyl cyclase → cAMP → PKA → insulin exocytosis (glucose-dependent). Parallel signaling: Gq/PLC/Ca²⁺ in some tissues; β-arrestin → biased endosomal cAMP prolongation; PI3K/Akt for beta-cell survival and proliferation. Exendin-4 (from Gila monster venom, 39 aa) is DPP-4-resistant and was the first non-mammalian GLP-1R agonist discovered. Exendin(9-39) is the canonical GLP-1R antagonist.
Approved GLP-1R agonists include: exenatide (twice daily), liraglutide (daily, also heart failure benefit), semaglutide (weekly SC or oral - first oral GLP-1R agonist), dulaglutide (weekly, Fc fusion), albiglutide (discontinued), and tirzepatide (GIP/GLP-1R dual, weekly - superior weight loss). Semaglutide 2.4 mg weekly (Wegovy) achieved ~15% body weight reduction in STEP trials. Oral semaglutide 50 mg achieved comparable weight loss in OASIS-1. Retatrutide (GIP/GLP-1/GCGR triple agonist, Phase 3) achieved ~24% weight reduction. For peptide research, the tractable recipes are: semaglutide-class C18 fatty diacid conjugates that extend half-life via albumin binding; Aib-substituted GLP-1 backbones for DPP-4 resistance; biased agonists that maximize endosomal cAMP over PM-cAMP to reduce nausea while preserving efficacy; exendin-4/GLP-1 chimeras for receptor subtype pharmacology; and GLP-1R/GCGR or GLP-1R/GIPR/GCGR dual/triple scaffolds using oxyntomodulin or tirzepatide as template.
HAEGTFTSDVSSYLEGQAAKEFIAWLVRGRG · 31 aa · @peptidemodel
| # | id | title | author | status | refs | ipSAE_d0chn | ♥ |
|---|---|---|---|---|---|---|---|
| 1 | pep-00016 | Semaglutide: Ozempic/Wegovy weight-loss & diabetes drug | pe@peptidemodel | 6 | — | 0 | |
| 2 | pep-00017 | Tirzepatide: Mounjaro/Zepbound weight-loss & diabetes drug | pe@peptidemodel | 6 | — | 0 | |
| 3 | pep-04439 | Exenatide: Byetta/Bydureon, first approved GLP-1 diabetes drug | pe@peptidemodel | 3 | — | 0 | |
| 4 | pep-10891 | Lixisenatide: Adlyxin/Lyxumia type 2 diabetes drug | pe@peptidemodel | 21 | — | 0 | |
| 5 | pep-10577 | GLP-1 (1-37): unprocessed precursor of the gut hormone behind Ozempic | pe@peptidemodel | 11 | — | 0 | |
| 6 | pep-10600 | Oxyntomodulin: natural gut hormone behind dual weight-loss drugs | pe@peptidemodel | 10 | — | 0 | |
| 7 | pep-10503 | Bone-building peptide from a cancer-linked protein (PTHrP 1-36) | pe@peptidemodel | 10 | — | 0 | |
| 8 | pep-10575 | GLP-1: the natural gut hormone behind Ozempic-class drugs | pe@peptidemodel | 9 | — | 0 | |
| 9 | pep-10525 | GLP-1 receptor blocker for research (Exendin 9-39) | pe@peptidemodel | 9 | — | 0 | |
| 10 | pep-00018 | Retatrutide: LY3437943, triple-action weight-loss drug (GIP/GLP-1/glucagon) | pe@peptidemodel | 5 | — | 1 | |
| 11 | pep-10569 | GLP-2: natural gut-lining growth hormone (Glucagon-like peptide-2) | pe@peptidemodel | 8 | — | 0 | |
| 12 | pep-04453 | Insulin B chain: half of the blood-sugar hormone insulin | pe@peptidemodel | 3 | — | 0 | |
| 13 | pep-04476 | Urocortin: natural stress & heart-protection hormone (UCN1) | pe@peptidemodel | 3 | — | 0 | |
| 14 | pep-10488 | β-CGRP: natural nerve-signaling peptide of the calcitonin family | pe@peptidemodel | 5 | — | 0 | |
| 15 | pep-10620 | Neuromedin S: brain clock and appetite-suppressing neuropeptide | pe@peptidemodel | 4 | — | 0 | |
| 16 | pep-10608 | Amylin: hunger-suppressing pancreas hormone (hamster research form) | pe@peptidemodel | 4 | — | 0 | |
| 17 | pep-10532 | GLP-1 receptor blocker (Exendin-4 (3-39)) | pe@peptidemodel | 4 | — | 0 | |
| 18 | pep-04450 | GLP-1: the gut hormone that inspired Ozempic and Wegovy (natural form) | pe@peptidemodel | 1 | — | 0 | |
| 19 | pep-10609 | Amylin (mouse/rat): safer rodent form of the meal-time blood-sugar hormone | pe@peptidemodel | 2 | — | 0 | |
| 20 | pep-10549 | Urocortin III: stress-recovery & heart-protective hormone | pe@peptidemodel | 2 | — | 0 |
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