钉合血管活性肠肽（VIP）衍生物可改善VPAC2激动作用和葡萄糖依赖性胰岛素分泌。
Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC2 Agonism and Glucose-Dependent Insulin Secretion.
作者信息
Giordanetto Fabrizio, Revell Jefferson D, Knerr Laurent, Hostettler Marie, Paunovic Amalia, Priest Claire, Janefeldt Annika, Gill Adrian
机构信息
Departments of Medicinal Chemistry and DMPK, AstraZeneca R&D, CVMD iMed , Mölndal, Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
Peptide Chemistry, ADPE, MedImmune Ltd , Granta Park, Cambridge CB21 6GH, United Kingdom.
出版信息
ACS Med Chem Lett. 2013 Oct 16;4(12):1163-8. doi: 10.1021/ml400257h. eCollection 2013 Dec 12.
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.
摘要
血管活性肠肽受体2（VPAC2）激动剂可刺激葡萄糖依赖性胰岛素分泌，使其成为治疗高血糖症和II型糖尿病的有吸引力的候选药物。血管活性肠肽（VIP）是一种内源性肽激素，可强效激动VPAC2。然而，VIP在体内血清半衰期短，药代动力学较差，且易受蛋白水解降解，这使得其作为治疗药物的开发具有挑战性。在此，我们研究了两种肽环化策略，即内酰胺化和烯烃复分解钉合，以及它们对VPAC2激动作用、肽二级结构、蛋白酶稳定性和细胞膜通透性的影响。发现了显示出VPAC2激动剂效力显著增强、葡萄糖依赖性胰岛素分泌活性增强以及螺旋含量增加的VIP类似物；然而，两种环化策略似乎均未影响所得肽的蛋白水解稳定性或细胞通透性。
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