Peak-2TZ 15mg

Peak-2TZ is a 39-amino acid linear peptide with a molecular formula of C₂₂₅H₃₄₈N₄₈O₆₈ and a molecular weight of approximately 4,813.45 Da. Engineered from a native glucose-dependent insulinotropic polypeptide (GIP) backbone, this compound incorporates targeted structural modifications that enable simultaneous agonism at both the GIP receptor (GIPR) and a second metabolic receptor.

Key structural modifications include: Position 2: Alpha-aminoisobutyric acid (Aib2) replacing alanine, conferring DPP-4 enzymatic resistance. Position 13: A second Aib substitution (Aib13) for enhanced stability. Position 20: Lysine conjugated to a C20 unsaturated fatty diacid moiety via a hydrophilic linker composed of L-gamma-glutamic acid and two 8-amino-3,6-dioxaoctanoic acid (OEG) spacers, enabling reversible serum albumin binding and extended circulating persistence. The C-terminus is amidated. Additional substitutions at positions 7 (Thr) and 18 (Ala) introduce secondary receptor character into the GIP backbone.

Peak-2TZ exhibits imbalanced and biased dual agonism as characterized in heterologous expression systems. At GIPR, it functions as a full agonist equipotent to native GIP in cAMP accumulation (EC₅₀ = 22.4 pM in low-receptor-density models), with full efficacy for beta-arrestin recruitment and receptor internalization. At the secondary receptor, it displays approximately 5-fold lower binding affinity, approximately 13-20-fold reduced cAMP potency (EC₅₀ = 934 pM), pronounced cAMP-biased signaling over beta-arrestin recruitment (<10% E_max), and impaired receptor internalization (<40% E_max).

Cryo-electron microscopy structures of the compound-bound receptor-G_s complexes have been resolved at 3.1 angstrom (GIPR) and 2.9 angstrom (secondary receptor) resolution. At GIPR, the compound adopts a similar alpha-helical conformation to native GIP with deep N-terminal insertion into the transmembrane domain. At the secondary receptor, weaker interactions with ECL2, loss of the Arg299(ECL2)-peptide contact, and an alternate Trp306 rotamer induced by the modified Tyr1 residue contribute to the reduced signaling efficacy.

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

In Vitro Research Applications: Peak-2TZ is employed in dual receptor pharmacology studies using HEK293 cells stably expressing human GIPR or the secondary target receptor. Standard assay platforms include cAMP accumulation assays (homogeneous time-resolved fluorescence or LANCE cAMP detection), beta-arrestin recruitment assays (PathHunter or NanoBiT complementation), ELISA-based receptor surface quantification for internalization kinetics, and GTP-gamma-S binding assays for G-protein activation profiling.

Signaling Pathway Studies: The imbalanced agonism profile makes this compound a valuable pharmacological tool for dissecting biased signaling at class B1 GPCRs. Comparative studies quantify bias factors between cAMP and beta-arrestin pathways at each receptor, enabling structure-activity analysis of multi-receptor agonist design. Molecular dynamics simulations reveal differential intramolecular hydrogen bonding between the lipid chain and Gln24 at GIPR (~40% occupancy) versus the secondary receptor (~18% occupancy), providing structural rationale for receptor-dependent pharmacology.

Molecular Characterization: Identity is confirmed by ESI-MS or MALDI-TOF mass spectrometry. Purity is determined by reversed-phase HPLC. Surface plasmon resonance (SPR) enables measurement of extracellular domain (ECD) binding kinetics (reported K_D values: GIPR ECD = 4.2 micromolar; secondary receptor ECD = 23 nM). DPP-4 resistance is quantifiable by incubation with recombinant enzyme and time-course chromatographic analysis.