A novel Hainan ConotoxinPotently Blocks a9alO Nicotinic Acetylcholine Receptors
作者单位：Key Laboratory of Tropical Biological ResourcesMinistry of EducationKey Lab for Marine Drug of HaikouHainan University Institute for Molecular BioscienceThe University of Queensland Shemyakin-Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of Sciences George E.Wahlen Veterans Affairs Medical Center and Departments of Biology and PsychiatryUniversity of Utah
会议名称：《第12届生物毒素研究及医药应用学术大会》
会议日期：2015年
学科分类：1007[医学-药学(可授医学、理学学位)] 100701[医学-药物化学] 10[医学]
摘 要：The a9al0 nicotinic acetylcholine receptor(nAChR) subtype is a recently identified target for the development of breast cancer chemotherapeutics and analgesics,particularly to treat neuropathic ***/function analyses of antagonists of this subtype are therefore essential for the development of specific therapeutic *** we report that αO-conotoxinGeXIVA(GeXVLA) from *** native to Hainan,China is a potent and selective antagonist of theα9α10 nAChR *** signal sequence of GeXVLA has high similarity with the O1-gene conotoxin *** predicted mature peptide(GeXVLA) has four Cys residues and its three disulfide isomers were *** pharmacologically characterized Ol-superfamily peptides contain six Cys residues are calcium,sodium or potassium channel ***,GeXTVA did not inhibit calcium channels but antagonized nAChRs,most potently on the α9α10nAChR subtype with an IC of 3.8 *** block was voltage dependent and kinetic analysis of toxin dissociation indicated that the binding site of GeXTVA does not overlap with that of the competitive antagonist ***,the most active disulfide isomer of GeXTVA is the bead isomer,comprising,according to NMR analysis,two well-resolved but uncoupled disulfide restrained *** ribbon isomer is almost as potent but has a more rigid structure built around a short *** contrast to most a-conotoxins,the globular isomer is the least potent and has a flexible,multi-conformational *** reduced mechanical hyperalgesia in the rat chronic constriction injury model of neuropathic pain,but had no effect on motor performance,warranting its further investigation as a possible therapeutic *** displays unique structural properties among other Conus peptides and represents a novel template for molecules active against neuropathic pain.