Effects of Cyclization on Stability, Structure, and Activity of 伪-Conotoxin RgIA at the 伪9伪10 Nicotinic Acetylcholine Receptor and GABAB Receptor

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• 作者：Reena Halai ; Brid Callaghan ; Norelle L. Daly ; Richard J. Clark ; David J. Adams ; David J. Craik
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 13, 2011
• 年：2011
• 卷：54
• 期：19
• 页码：6984-6992
• 全文大小：982K
• 年卷期：v.54,no.19(October 13, 2011)
• ISSN：1520-4804

文摘

伪-Conotoxin RgIA is of interest as a lead in the development of drugs for neuropathic pain. It modulates the 伪9伪10 nicotinic acetylcholine receptor (nAChR) and the GABA_B receptor, both of which are implicated in antinociception. However, because of its peptidic nature, RgIA is potentially susceptible to generic problems encountered by peptide-based drugs of poor oral bioavailability, short biological half-life, and low stability. Here, we improved the biopharmaceutical properties of RgIA by backbone cyclization using 3鈥? residue peptidic linkers. Cyclization with a six-residue linker does not perturb the overall structure of RgIA, improves selectivity for the GABA_B receptor over the 伪9伪10 nAChR, and improves stability in human serum. The results provide insights to further improve the therapeutic properties of RgIA and other conotoxins being considered as drug leads and confirm that cyclization is a readily applicable strategy to improve the stability of peptides with proximate N- and C-termini.