AMY (CG) / GLP-3 (RT)

High-resolution structural methods have been applied to characterize how each blend component engages its target receptors. For AMY (CG), cryo-EM studies (Cao et al., 2025, Nature Communications; Gu et al., 2026, Acta Pharmacologica Sinica) resolved the peptide's binding to CTR and amylin receptor heteromers (CTR–RAMP1/2/3), examining how the lipidated analog's interactions at calcitonin-family receptor extracellular domains compare to those of the native amylin peptide sequence. For GLP-3 (RT), parallel cryo-EM work (Li et al., 2024, Cell Discovery) determined structures of the peptide bound independently to GLP-1R, GIPR, and GCGR, mapping how its modified N-terminal region and fatty-acid side chain engage each receptor's orthosteric pocket and extracellular loops. Mutation and functional assays in those studies identified key receptor contacts — hydrogen-bond and hydrophobic interactions within the peptide's N-terminal region — that characterize GLP-3 (RT)'s binding profile across the three receptors. Together, these structural investigations document the molecular basis for each component's receptor engagement across two distinct class B GPCR families.

Cell-based assays have been used to profile the receptor pharmacology of both blend components. AMY (CG) stimulates cAMP-linked signaling through CTR and AMY1-3R subtypes in transfected cell models; pharmacological profiling has characterized the receptor selectivity and signal transduction of the lipidated analog relative to the non-lipidated parent peptide. The medicinal-chemistry study of AMY (CG) (Kruse et al., 2021, Journal of Medicinal Chemistry) described the effects of sequence modifications — proline substitutions, disulfide cyclization, and C20 fatty-diacid acylation — on amylin receptor pharmacology assays and aggregation propensity. GLP-3 (RT) has been examined in cAMP signaling assays across GLP-1R, GIPR, and GCGR in CHO and other cell-line models, with comparative profiling against native GIP, GLP-1, and glucagon peptides and against single- and dual-agonist reference compounds to characterize the breadth of its three-receptor engagement (Coskun et al., 2022, Cell Metabolism). That study also assessed GLP-3 (RT) in in vitro adipocyte models as part of its receptor-activation characterization.

Rodent studies have examined the metabolic pharmacology of each component. The Coskun et al. (2022) discovery study investigated GLP-3 (RT) in established rodent metabolic models, measuring body-composition and energy-metabolism endpoint panels in comparison with dual-agonist reference profiles, and characterized the contribution of GCGR receptor engagement to the phenotype observed in those models. AMY (CG) analogs were evaluated in rodent metabolic models during the medicinal-chemistry optimization described by Kruse et al. (2021), with assays examining how sequence changes — proline substitutions, lipidation chain length — affected amyloid aggregation propensity and receptor engagement characteristics. Both peptides have been engineered for prolonged duration of action in animal studies, consistent with their albumin-binding lipidation strategies.

Human research on these peptides has focused on pharmacokinetics, safety, and early-phase endpoint assessment. A Phase 1 study of AMY (CG) (Nielsen et al., 2026, Clinical Pharmacokinetics) characterized single-dose plasma exposure across cohorts with normal kidney function, renal impairment, and hepatic impairment, examining whether organ dysfunction alters total AMY (CG) exposure. For GLP-3 (RT), a Phase 2 placebo-controlled trial (Jastreboff et al., 2023, New England Journal of Medicine; NCT04881760) examined metabolic, glycemic, and safety endpoints over 24 and 48 weeks across multiple dose-level study arms. Walker et al. (2025, Nature Reviews Endocrinology) provide a narrative review contextualizing amylin analog pharmacology within the calcitonin-peptide receptor family biology. Larger Phase 2 and 3 programs for GLP-3 (RT) examining metabolic and glycemic endpoints are ongoing.