Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia

Heng Zhang, Jia-Jia Lin, Ya-Kai Xie, Xiu-Zu Song, Jia-Yi Sun, Bei-Lei Zhang, Yun-Kun Qi (), Zhen-Zhong Xu () and Fan Yang ()
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Heng Zhang: Zhejiang University School of Medicine
Jia-Jia Lin: Zhejiang University Medical Center
Ya-Kai Xie: Zhejiang University Medical Center
Xiu-Zu Song: The Third People’s Hospital of Hangzhou
Jia-Yi Sun: The Third People’s Hospital of Hangzhou
Bei-Lei Zhang: The Third People’s Hospital of Hangzhou
Yun-Kun Qi: Qingdao University
Zhen-Zhong Xu: Zhejiang University Medical Center
Fan Yang: Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Transient receptor potential vanilloid 1 (TRPV1) ion channel is a classic analgesic target, but antagonists of TRPV1 failed in clinical trials due to their side effects like hyperthermia. Here we rationally engineer a peptide s-RhTx as a positive allosteric modulator (PAM) of TRPV1. Patch-clamp recordings demonstrate s-RhTx selectively potentiated TRPV1 activation. s-RhTx also slows down capsaicin-induced desensitization of TRPV1 in the presence of calcium to cause more calcium influx in TRPV1-expressing cells. In addition, our thermodynamic mutant cycle analysis shows that E652 in TRPV1 outer pore specifically interacts with R12 and K22 in s-RhTx. Furthermore, we demonstrate in vivo that s-RhTx exhibits long-lasting analgesic effects in noxious heat hyperalgesia and CFA-induced chronic inflammatory pain by promoting the reversible degeneration of intra-epidermal nerve fiber (IENF) expressing TRPV1 channels in mice, while their body temperature remains unaffected. Our results suggest s-RhTx is an analgesic agent as a PAM of TRPV1.

Date: 2023
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DOI: 10.1038/s41467-022-34817-1

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