Garrison, Catherine, Guan, Wendy, Kato, Mitsunori, Tamsett, Thomas, Patel, Tej, Sun, Yishan and Pathak, Tejas (2019) SAR evaluation of wasp toxin -PMTX leads to analogs with superior efficacy for human neuronal sodium channels. ACS Medicinal Chemistry Letters. ISSN 1948-58751948-5875

Abstract

ABSTRACT: Beta-pompilidotoxin (-PMTX) is a 13-amino acid wasp venom peptide that activates human neuronal sodium channel NaV1.1 with weak efficacy (2% activation at 370 nM of -PMTX). Through rational design of -PMTX analogs, we have identified peptides with significant improvement of efficacy on human NaV1.1 (145% activation at 370 nM of peptide 18). The underlying structural activity relationship suggests importance of charge interactions (from residue Lys-3) and lipophilic interac-tions (from residue Phe-7 and Ser-11). Three top-ranked analogs showed parallel efficacy 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 neuro-pharmacological tools.

Item Type:	Article
Date Deposited:	24 Jan 2020 00:45
Last Modified:	24 Jan 2020 00:45
URI:	https://oak.novartis.com/id/eprint/40667