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

Garrison, Catherine and Guan, Wendy and Kato, Mitsunori and Tamsett, Thomas and Patel, Tej and 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

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