Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors.

A 13 aa residue voltage-gated sodium (Na) channel inhibitor peptide, Pn, containing 2 disulfide bridges was designed by using a chimeric approach. This approach was based on a common pharmacophore deduced from sequence and secondary structural homology of 2 Na inhibitors: Conus kinoshitai toxin IIIA, a 14 residue cone snail peptide with 3 disulfide bonds, and Phoneutria nigriventer toxin 1, a 78 residue spider toxin with 7 disulfide bonds. As with the parent peptides, this novel Na channel inhibitor was active on Na1.2. Through the generation of 3 series of peptide mutants, we investigated the role of key residues and cyclization and their influence on Na inhibition and subtype selectivity. Cyclic PnCS1, a 10 residue peptide cyclized via a disulfide bond, exhibited increased inhibitory activity toward therapeutically relevant Na channel subtypes, including Na1.7 and Na1.9, while displaying remarkable serum stability. These peptides represent the first and the smallest cyclic peptide Na modulators to date and are promising templates for the development of toxin-based therapeutic agents.-Peigneur, S., Cheneval, O., Maiti, M., Leipold, E., Heinemann, S. H., Lescrinier, E., Herdewijn, P., De Lima, M. E., Craik, D. J., Schroeder, C. I., Tytgat, J. Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors.