The road to evolution of ProTx2: how to be a subtype-specific inhibition of human Nav1.7

Fan Zhao; Yuanyuan Liu; Yiyu Liu; Qi Ye; Hongtao Yang; Mingze Gui; Yongbo Song

doi:10.3389/fphar.2024.1374183

The road to evolution of ProTx2: how to be a subtype-specific inhibition of human Na_v1.7

Front Pharmacol. 2024 May 2:15:1374183. doi: 10.3389/fphar.2024.1374183. eCollection 2024.

Authors

Fan Zhao¹, Yuanyuan Liu¹, Yiyu Liu¹, Qi Ye¹, Hongtao Yang¹, Mingze Gui¹, Yongbo Song¹

Affiliation

¹ School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.

Abstract

The human voltage-gated sodium channel Na_v1.7 is a widely proven target for analgesic drug studies. ProTx2, a 30-residue polypeptide from Peruvian green tarantula venom, shows high specificity to activity against human Na_v1.7, suggesting its potential to become a non-addictive analgesic. However, its high sensitivity to human Na_v1.4 raises concerns about muscle side effects. Here, we engineered three mutants (R13A, R13D, and K27Y) of ProTx2 to evaluate their pharmacological activities toward Na_v1.7 and Na_v1.4. It is demonstrated that the mutant R13D maintained the analgesic effect in mice while dramatically reducing its muscle toxicity compared with ProTx2. The main reason is the formation of a strong electrostatic interaction between R13D and the negatively charged amino acid residues in DII/S3-S4 of Na_v1.7, which is absent in Na_v1.4. This study advances our understanding and insights on peptide toxins, paving the way for safer, effective non-addictive analgesic development.

Keywords: ProTx2; analgesia; structure optimization; toxin; voltage-gated sodium ion channel.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported by the Basic Scientific Research Project of Colleges and University of Liaoning Provincial Department of Education (LJKMZ20221359, LJKZ0936), PhD research startup foundation of Liaoning Province (2023-BS-116), and the National Natural Science Foundation of China (grant number: 81973227).