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

被引：35

作者：

Giordanetto, Fabrizio ^{[1
]}

Revell, Jefferson D. ^{[3
]}

Knerr, Laurent ^{[1
]}

Hostettler, Marie ^{[4
]}

Paunovic, Amalia ^{[5
]}

Priest, Claire ^{[6
]}

Janefeldt, Annika ^{[2
]}

Gill, Adrian ^{[1
]}

机构：

[1] AstraZeneca R&D, CVMD iMed, Dept Med Chem, SE-43183 Molndal, Sweden

[2] AstraZeneca R&D, CVMD iMed, DMPK, SE-43183 Molndal, Sweden

[3] MedImmune Ltd, Peptide Chem, ADPE, Cambridge CB21 6GH, England

[4] Ecole Natl Super Chim Montpellier, F-34296 Montpellier 5, France

[5] AstraZeneca R&D, Reagents & Assay Dev, Discovery Sci, SE-43183 Molndal, Sweden

[6] AstraZeneca R&D, High Content Biol, Discovery Sci, Macclesfield SK10 4TG, Cheshire, England

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 12期

关键词：

VIP; vasoactive intestinal peptide; VPAC; peptide agonist; insulin secretion; glucose tolerance; stapled peptide; lactamized peptide; ring-closing metathesis; CYCLASE-ACTIVATING PEPTIDE; RING-CLOSING METATHESIS; PARKINSONS-DISEASE; HELICAL PEPTIDES; RECEPTOR; POLYPEPTIDE; GLUCAGON; STABILITY; POTENT; PACAP;

D O I：

10.1021/ml400257h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Agonists of vasoactive intestinal peptide receptor 2 (VPAC(2)) 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 VPAC(2). 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 VPAC(2) agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC(2) 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.

引用

页码：1163 / 1168

页数：6

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