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

A 13 aa residue voltage-gated sodium (Na_V) 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_V 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_V channel inhibitor was active on Na_V1.2. Through the generation of 3 series of peptide mutants, we investigated the role of key residues and cyclization and their influence on Na_V inhibition and subtype selectivity. Cyclic PnCS1, a 10 residue peptide cyclized via a disulfide bond, exhibited increased inhibitory activity toward therapeutically relevant Na_V channel subtypes, including Na_V1.7 and Na_V1.9, while displaying remarkable serum stability. These peptides represent the first and the smallest cyclic peptide Na_V 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.