Structure-Activity Relationship Evaluation of Wasp Toxin β-PMTX Leads to Analogs with Superior Activity for Human Neuronal Sodium Channels

Catherine E Garrison; Wendy Guan; Mitsunori Kato; Thomas Tamsett; Tajesh Patel; Yishan Sun; Tejas P Pathak

doi:10.1021/acsmedchemlett.9b00415

Structure-Activity Relationship Evaluation of Wasp Toxin β-PMTX Leads to Analogs with Superior Activity for Human Neuronal Sodium Channels

ACS Med Chem Lett. 2019 Oct 25;11(3):353-357. doi: 10.1021/acsmedchemlett.9b00415. eCollection 2020 Mar 12.

Authors

Catherine E Garrison¹, Wendy Guan¹, Mitsunori Kato¹, Thomas Tamsett¹, Tajesh Patel¹, Yishan Sun¹, Tejas P Pathak¹

Affiliation

¹ Global Discovery Chemistry and Neuroscience, Novartis Institutes for BioMedical Research, 22 Windsor Street, Cambridge, Massachusetts 02139, United States.

Abstract

Beta-pompilidotoxin (β-PMTX) is a 13-amino acid wasp venom peptide that activates human neuronal sodium channel Na_V1.1 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_V1.1 (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_V1.2/1.3/1.6/1.7) but not muscular subtypes (Na_V1.4/1.5). Finally, we found that analog 16 could partially rescue the pharmacological block imposed by Na_V1.1/1.3 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.