Structure and Activity of (2,8)-Dicarba-(3,12)-cystino a-ImI, an a-Conotoxin Containing a Nonreducible Cystine Analogue.
作者
MacRaild, Christopher A.;Illesinghe, Jayamini;van Lierop, Bianca J.;Townsend, Amanda L.;Chebib, Mary;Livett, Bruce G.;Robinson, Andrea J.;Norton, Raymond S.;
[摘要]：The a-conotoxins are potent and selective antagonists of nicotinic acetylcholine receptors (nAChR). Exploitation of these and other peptides in research and clin. settings has been hampered by the lability of the disulfide bridges that are essential for toxin structure and activity. One soln. to this problem is replacement of cystine bridges with non-reducible dicarba linkages. We explore this approach by detg. the soln. structure and functional characteristics of a dicarba analog of the a-conotoxin a-ImI, (2,8)-dicarba-(3,12)-cystino a-ImI. The structure of the dicarba analog was similar to that of native a-ImI, with differences attributable to the different covalent geometry of the disulfide and dicarba bridges. Dicarba-a-ImI maintained inhibitory activity of nAChR comparable to that of native a-ImI in two in vitro assays. These findings confirm the potential of the dicarba linkage to improve stability while maintaining a-conotoxin function.
