Open AccessStructure–Activity Relationship Evaluation of Wasp Toxin β-PMTX Leads to Analogs with Superior Activity for Human Neuronal Sodium Channels
Author(s) -
Catherine E. Garrison,
Wendy Guan,
Mitsunori Kato,
Thomas J. Tamsett,
Tajesh Patel,
Yishan Sun,
Tejas P. Pathak
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00415
Subject(s) - sodium channel , peptide , venom , nav1 , chemistry , gabaergic , premovement neuronal activity , pharmacology , sodium channel blocker , sodium , neuroscience , biophysics , biochemistry , biology , receptor , organic chemistry
Beta-pompilidotoxin (β-PMTX) is a 13-amino acid wasp venom peptide that activates human neuronal sodium channel Na V 1.1 with weak activity (40% activation at 3.3 μM of β-PMTX). Through rational design of β-PMTX analogs, we have identified peptides with significantly improved activity on human Na V 1.1 (1170% activation at 3.3 μM of peptide 18 ). The underlying structure-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 Na V 1.2/1.3/1.6/1.7) but not muscular subtypes (Na V 1.4/1.5). Finally, we found that analog 16 could partially rescue the pharmacological block imposed by Na V 1.1/1.3 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.