Retatrutide 10mg

Retatrutide (LY3437943, CAS 2381089-83-2) is a 39-amino acid synthetic peptide with a molecular formula of C₂₁₁H₃₂₆N₅₀O₆₇S₂ and a molecular weight of 4,703.34 Da. Built from a GIP peptide backbone, retatrutide achieves simultaneous agonism at three distinct G-protein-coupled receptors: the GIP receptor (GIPR), glucagon-like peptide-1 receptor (GLP-1R), and glucagon receptor (GCGR).

The peptide incorporates several non-natural amino acid substitutions critical to its multi-receptor activity profile. Positions 2 and 20: Alpha-aminoisobutyric acid (Aib) substitutions: Aib2 provides DPP-4 enzymatic cleavage resistance, while Aib20 optimizes GIPR activity and developability. Position 13: Alpha-methyl-L-leucine (alphaMeL), which promotes selectivity tuning across the three receptor targets. Position 20: Lysine is further modified with a linker composed of AEEA (2-[2-(2-aminoethoxy)ethoxy]acetic acid) spacer, gamma-glutamic acid, and a C20 fatty diacid chain enabling reversible albumin binding. The C-terminus is modified as L-serinamide.

In vitro cAMP accumulation assays demonstrate that retatrutide functions as a full agonist at all three receptors with the following potency profile: GIPR EC₅₀ = 0.064 nM (comparable to native GIP), GLP-1R EC₅₀ = 0.775 nM (2.5-fold less potent than GLP-1(7-36)NH₂), and GCGR EC₅₀ = 5.79 nM (2.9-fold less potent than native glucagon). The glucagon receptor component is the defining structural differentiator from dual-agonist compounds, as GCGR signaling activates hepatic adenylyl cyclase through a distinct G_s-coupled pathway.

Cryo-electron microscopy structures of retatrutide bound to GLP-1R, GIPR, and GCGR-G_s complexes reveal that triple agonism is achieved through conserved peptide-receptor interactions at the transmembrane core combined with receptor-specific conformational adaptations, particularly in extracellular loop 1 (ECL1). This structural data provides a molecular framework for understanding multi-target GPCR agonist design.

Supplied as a lyophilized powder for in vitro research applications only. Not for human or veterinary use.

In Vitro Research Applications: Retatrutide is used in comparative receptor pharmacology studies employing cell lines expressing human GCGR, GIPR, and GLP-1R individually. Standard assay formats include cAMP accumulation assays (HTRF or LANCE detection platforms) for potency determination at each receptor, beta-arrestin recruitment assays for pathway bias characterization, and receptor internalization assays via ELISA-based surface receptor quantification. The compound enables direct comparison of signaling outputs across all three incretin/glucagon receptor family members in parallel.

Signaling Pathway Studies: The triple agonist profile makes retatrutide a uniquely valuable tool for dissecting receptor cross-talk and comparative GPCR signaling analysis. Research applications include quantification of G_s-coupled cAMP generation kinetics across receptor subtypes, comparative dose-response profiling to establish selectivity ratios (GIPR:GLP-1R:GCGR), and structure-activity relationship studies examining how specific amino acid modifications (particularly alphaMeL13 and Aib20) differentially affect potency at each receptor target.

Molecular Characterization: Identity confirmation is performed via ESI-MS or MALDI-TOF mass spectrometry (expected MW 4,703.34 Da). Purity is assessed by reversed-phase HPLC. The triple-receptor binding profile can be characterized by radioligand competition assays or surface plasmon resonance using purified receptor extracellular domains. Peptide stability is evaluated by DPP-4 degradation kinetics and serum stability assays with time-course HPLC monitoring.

References

1. Coskun T, et al. (2022) LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab, 34(9):1234-1247. PMID: 35985340
2. Wang X, et al. (2024) Structural insights into the triple agonism at GLP-1R, GIPR and GCGR manifested by retatrutide. Cell Discov, 10:72.
3. Urva S, et al. (2022) LY3437943 (retatrutide), a novel triple GIP, GLP-1, and glucagon receptor agonist: pharmacokinetics and receptor activation profile. Diabetes, 71(Supplement_1):76-OR.