Polypeptide ?-conotoxin GVIA as a basis for new analgesic and neuroprotective agents

The ω-conotoxins are small polypeptides (of around 25 residues) cross-linked by three disulfide bonds. At least two of these, ω-conotoxins GVIA and MVIIA, are potent and selective blockers of N-type voltage-gated calcium channels. Administered intravenously, GVIA causes postural hypotension and blocks cardiac sympathetic and vagal reflexes, homeostatic cardiovascular effects that should normally be preserved. Administered intrathecally, MVIIA and GVIA are analgesic in acute, chronic, and neuropathic pain models, and protective following ischaemia-induced neuronal injury. We have determined the three-dimensional structure of GVIA and mapped onto that structure its calcium channel binding surface. This information is now being used in the structure-based design of truncated and stabilised peptidic analogues of GVIA and in the development of peptidomimetic analogues. This article summarizes these data and outlines the strategies being pursued in the development of low molecular weight analogues for therapeutic applications. Drug Dev. Res. 46:206–218, 1999.