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

Author

Listed:
  • Heng Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare)

  • Jia-Jia Lin

    (Zhejiang University Medical Center
    Zhejiang University School of Medicine)

  • Ya-Kai Xie

    (Zhejiang University Medical Center
    Zhejiang University School of Medicine)

  • 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
    Zhejiang University School of Medicine)

  • Fan Yang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare)

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.

Suggested Citation

  • Heng Zhang & Jia-Jia Lin & Ya-Kai Xie & Xiu-Zu Song & Jia-Yi Sun & Bei-Lei Zhang & Yun-Kun Qi & Zhen-Zhong Xu & Fan Yang, 2023. "Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-34817-1
    DOI: 10.1038/s41467-022-34817-1
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    References listed on IDEAS

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