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

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

ACS Med Chem Lett. 2019 Oct 25;11(3):353-357.

PMID: 32184969

Abstract:

Beta-pompilidotoxin (β-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 μM of β-PMTX). Through rational design of β-PMTX analogs, we have identified peptides with significantly improved activity on human NaV1.1 (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 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP313254512	ICA-121431		313254-51-2	Price

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