A case study of 2,2-dimethylthiazolidine as locked cis proline amide bond: synthesis, NMR and molecular modeling studies of a δ-conotoxin EVIA peptide analog

Abstract

The δ-conotoxin EVIA from the Conus ermineus venom, a recently characterized toxin, exhibits cis–trans isomerism of the Leu¹²-Pro¹³ bond associated with the triggering of its biological activity. In this paper we use the pseudoproline concept to target the presumed bioactive cis conformation. We report the design and the synthesis of loop 2 analogs from residue 8 to 18 containing either the cis-inducing Cys(Ψ^Me,MePro)¹³ unit 1 or the natural proline residue 2. NMR studies in water and molecular modeling allowed us to identify the amide bond “locked” in a cis conformation for 1 as in the suggested bioactive form of the natural toxin.