A single stable topological stereoisomer of a two disulfide conotoxin mimetic demonstrates full potency on the human norepinephrine transporter

Conotoxin χ-Mr1a, a 13 residue conotoxin that has two disulfide bonds in the ribbon fold, is found in the venom of the predatory marine snail, C. marmoreus. It noncompetitively inhibits the human norepinephrine transporter (hNET), leading to reduced allodynia in animal models of neuropathic pain. Rational design was used to prune conotoxin χ-Mr1a while maintaining the pharmacophore that led to the development of an equipotent mimetic (half maximal inhibitory concentration, IC50: 760 nM). Surpris