SAR evaluation of wasp toxin β-PMTX leads to analogs with superior activity for human neuronal sodium channels

Beta-pompilidotoxin (-PMTX) is a 13-amino acid wasp venom peptide that activates human neuronal sodium channel NaV1.1 with weak activity (40% activation at 3.3 M of -PMTX). Through rational design of -PMTX analogs, we have identified peptides with significantly improved activity on human NaV1.1 (1170% activation at 3.3 M of peptide). The underlying structural activity relationship suggests importance of charge interactions (from residue Lys-3) and lipophilic interactions (from residue Phe-7 and Ser-11). Three top-ranked analogs showed parallel activity improvement for other neuronal sodium channels (human NaV1.2/1.3/1.6/1.7) but not muscular subtypes (NaV1.4/1.5). Finally, we found that analog 16 could partially rescue the pharmacological block imposed by NaV1.1/1.3 selective inhibitor ICA-121431 in cultured mouse cortical GABAergic neurons, demonstrating an activating effect of this peptide on native neuronal sodium channels and its potential utility as a neuropharmacological tool.