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From traditional medicine to targeted therapy: Structure-activity relationship-guided optimization of scorpion toxin

Yiyu Liu¹, Yuanyuan Liu¹, Yunxia Liu¹

¹School of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China.

Journal of Ethnopharmacology

|July 4, 2025

Abstract

Ethnopharmacological Relevance:

Scorpion toxins, as critical bioactive components in traditional Chinese medicine (TCM), show potential as non-addictive analgesics targeting the pain-associated sodium channels (Na_V1.7, Na_V1.8, and Na_V1.9). However, their clinical application is limited by off-target effects on the subtypes distributed in cardiac (Na_V1.5) and skeletal muscle (Na_V1.4).

Aim Of The Study:

This study aims to enhance the analgesic activity and reduce the adverse effects of scorpion toxin DKK2 through modern pharmacological research methods, thereby improving its potential for clinical application.

Methods:

Structure-activity relationships (SAR) between DKK2 and different Na_V subtypes were investigated through computer simulations. Saturation mutagenesis of critical residues on the toxin was used to produce high subtype selectivity mutants. Analgesic activity was evaluated in vivo using formalin-induced paw licking test, while adverse reactions were assessed by forced swimming test, blood assay, and cell viability assays. In addition, whole-cell patch-clamp was employed to clarify the inhibition of DKK2 and its mutants against Na_V1.4, Na_V1.5, and Na_V1.7.

Results:

Residue 18 of DKK2 was identified as a key determinant of its Na_V subtype selectivity. The N18W mutant demonstrated significantly enhanced analgesic effects with reduced adverse effects on the skeletal and cardiac muscle compared to the wild-type DKK2.

Conclusion:

By integrating TCM-derived toxin insights with SAR-guided mutagenesis, we developed a scorpion toxin mutant (N18W) with optimized analgesic properties and minimized off-target effects. This study provides a translational framework for refining traditional medicine into targeted therapeutics.

Keywords:

Analgesic activity Rational design Scorpion toxin Structure-activity relationship analysis Voltage-gated sodium channel

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