Document Report Card

ID: ALA3102798

Journal: ACS Med Chem Lett

Title: Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion.

Authors: Giordanetto F, Revell JD, Knerr L, Hostettler M, Paunovic A, Priest C, Janefeldt A, Gill A.

Abstract: Agonists of vasoactive intestinal peptide receptor 2 (VPAC2) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC2. However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging. Here, we investigated two peptide cyclization strategies, lactamisation and olefin-metathesis stapling, and their effects on VPAC2 agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC2 agonist potency, glucose-dependent insulin secretion activity, and increased helical content were discovered; however, neither cyclization strategy appeared to effect proteolytic stability or cell permeability of the resulting peptides.

CiteXplore: 24900623

DOI: 10.1021/ml400257h