Peak-3RT 10mg 30mg

Peak-3RT 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, this compound achieves simultaneous agonism at three distinct G-protein-coupled receptors: the GIP receptor (GIPR), a secondary metabolic receptor, and the 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 Peak-3RT functions as a full agonist at all three receptors with the following potency profile: GIPR EC₅₀ = 0.064 nM (comparable to native GIP), secondary receptor EC₅₀ = 0.775 nM, 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 Peak-3RT bound to all three receptor-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: Peak-3RT is used in comparative receptor pharmacology studies employing cell lines expressing human GCGR, GIPR, and secondary metabolic receptors 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 receptor family members in parallel.

Signaling Pathway Studies: The triple agonist profile makes Peak-3RT 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, 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.