title: Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion.
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.
authors.affiliation: Departments of Medicinal Chemistry and DMPK, AstraZeneca R&D, CVMD iMed , Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Giordanetto
authors.affiliation: Peptide Chemistry, ADPE, MedImmune Ltd , Granta Park, Cambridge CB21 6GH, United Kingdom.
authors.forename: Jefferson D
authors.initials: JD
authors.lastname: Revell
authors.affiliation: Departments of Medicinal Chemistry and DMPK, AstraZeneca R&D, CVMD iMed , Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Laurent
authors.initials: L
authors.lastname: Knerr
authors.affiliation: Ecole Nationale Supérieure de Chimie de Montpellier, 8 Rue de l'Ecole Normale, 34296 Montpellier, Cedex 5, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Hostettler
authors.affiliation: Reagents and Assay Development, AstraZeneca R&D, Discovery Sciences , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Amalia
authors.initials: A
authors.lastname: Paunovic
authors.affiliation: High Content Biology, AstraZeneca R&D, Discovery Sciences , 14F4 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Priest
authors.affiliation: Departments of Medicinal Chemistry and DMPK, AstraZeneca R&D, CVMD iMed , Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Janefeldt
authors.affiliation: Departments of Medicinal Chemistry and DMPK, AstraZeneca R&D, CVMD iMed , Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Adrian
authors.initials: A
authors.lastname: Gill
keywords: VIP; VPAC; glucose tolerance; insulin secretion; lactamized peptide; peptide agonist; ring-closing metathesis; stapled peptide; vasoactive intestinal peptide