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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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    1. Michael J. Caterina & Mark A. Schumacher & Makoto Tominaga & Tobias A. Rosen & Jon D. Levine & David Julius, 1997. "The capsaicin receptor: a heat-activated ion channel in the pain pathway," Nature, Nature, vol. 389(6653), pages 816-824, October.
    2. Shilong Yang & Fan Yang & Ningning Wei & Jing Hong & Bowen Li & Lei Luo & Mingqiang Rong & Vladimir Yarov-Yarovoy & Jie Zheng & KeWei Wang & Ren Lai, 2015. "A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    3. Erhu Cao & Maofu Liao & Yifan Cheng & David Julius, 2013. "TRPV1 structures in distinct conformations reveal activation mechanisms," Nature, Nature, vol. 504(7478), pages 113-118, December.
    4. Lizhen Xu & Yalan Han & Xiaoying Chen & Aerziguli Aierken & Han Wen & Wenjun Zheng & Hongkun Wang & Xiancui Lu & Zhenye Zhao & Cheng Ma & Ping Liang & Wei Yang & Shilong Yang & Fan Yang, 2020. "Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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