IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-022-34817-1.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34817-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-34817-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Maxim V Nikolaev & Natalia A Dorofeeva & Margarita S Komarova & Yuliya V Korolkova & Yaroslav A Andreev & Irina V Mosharova & Eugene V Grishin & Denis B Tikhonov & Sergey A Kozlov, 2017. "TRPV1 activation power can switch an action mode for its polypeptide ligands," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-16, May.
    2. Barbara Storti & Carmine Di Rienzo & Francesco Cardarelli & Ranieri Bizzarri & Fabio Beltram, 2015. "Unveiling TRPV1 Spatio-Temporal Organization in Live Cell Membranes," PLOS ONE, Public Library of Science, vol. 10(3), pages 1-17, March.
    3. Arthur Neuberger & Mai Oda & Yury A. Nikolaev & Kirill D. Nadezhdin & Elena O. Gracheva & Sviatoslav N. Bagriantsev & Alexander I. Sobolevsky, 2023. "Human TRPV1 structure and inhibition by the analgesic SB-366791," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    4. Zakir, HM & Mostafeezur, RM & Suzuki, A & Hitomi, S & Maeda, T & Seo, K & Yamada, Y & Yamamura, K & Lev, S & Binshtok, AM & Iwata, K & Kitagawa, J, 2012. "Expression of TRPV1 channels after nerve injury provides an essential delivery tool for neuropathic pain attenuation," MPRA Paper 50539, University Library of Munich, Germany.
    5. Hiroki Ota & Kimiaki Katanosaka & Shiori Murase & Makiko Kashio & Makoto Tominaga & Kazue Mizumura, 2013. "TRPV1 and TRPV4 Play Pivotal Roles in Delayed Onset Muscle Soreness," PLOS ONE, Public Library of Science, vol. 8(6), pages 1-10, June.
    6. Hossain Md Zakir & Rahman Md Mostafeezur & Akiko Suzuki & Suzuro Hitomi & Ikuko Suzuki & Takeyasu Maeda & Kenji Seo & Yoshiaki Yamada & Kensuke Yamamura & Shaya Lev & Alexander M Binshtok & Koichi Iwa, 2012. "Expression of TRPV1 Channels after Nerve Injury Provides an Essential Delivery Tool for Neuropathic Pain Attenuation," PLOS ONE, Public Library of Science, vol. 7(9), pages 1-12, September.
    7. Petra I Baeumler & Johannes Fleckenstein & Shin Takayama & Michael Simang & Takashi Seki & Dominik Irnich, 2014. "Effects of Acupuncture on Sensory Perception: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 9(12), pages 1-40, December.
    8. Do Hoon Kwon & Feng Zhang & Justin G. Fedor & Yang Suo & Seok-Yong Lee, 2022. "Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    9. Filomena Perri & Adriana Coricello & James D. Adams, 2020. "Monoterpenoids: The Next Frontier in the Treatment of Chronic Pain?," J, MDPI, vol. 3(2), pages 1-20, May.
    10. Luciano Maria Catalfamo & Giulia Marrone & Michele Basilicata & Ilaria Vivarini & Vincenza Paolino & David Della-Morte & Francesco Saverio De Ponte & Francesca Di Daniele & Domenico Quattrone & Danilo, 2022. "The Utility of Capsicum annuum L. in Internal Medicine and In Dentistry: A Comprehensive Review," IJERPH, MDPI, vol. 19(18), pages 1-20, September.
    11. Ruth A. Pumroy & Anna D. Protopopova & Tabea C. Fricke & Iris U. Lange & Ferdinand M. Haug & Phuong T. Nguyen & Pamela N. Gallo & Bárbara B. Sousa & Gonçalo J. L. Bernardes & Vladimir Yarov-Yarovoy & , 2022. "Structural insights into TRPV2 activation by small molecules," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    12. Jongdae Won & Jinsung Kim & Hyeongseop Jeong & Jinhyeong Kim & Shasha Feng & Byeongseok Jeong & Misun Kwak & Juyeon Ko & Wonpil Im & Insuk So & Hyung Ho Lee, 2023. "Molecular architecture of the Gαi-bound TRPC5 ion channel," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    13. Xiaolong Gao & Philipp A. M. Schmidpeter & Vladimir Berka & Ryan J. Durham & Chen Fan & Vasanthi Jayaraman & Crina M. Nimigean, 2022. "Gating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    14. Arthur Neuberger & Kirill D. Nadezhdin & Alexander I. Sobolevsky, 2021. "Structural mechanisms of TRPV6 inhibition by ruthenium red and econazole," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    15. Nolwenn Tessier & Mallory Ducrozet & Sylvie Ducreux & Fabien Van Coppenolle & Julien Faure, 2018. "Pathophysiological Role of Trpv1 In Malignant Hyperthermia: Identification of New Variants," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 12(1), pages 8891-8893, December.
    16. Liying Zhang & Charlotte Simonsen & Lucie Zimova & Kaituo Wang & Lavanya Moparthi & Rachelle Gaudet & Maria Ekoff & Gunnar Nilsson & Ute A. Hellmich & Viktorie Vlachova & Pontus Gourdon & Peter M. Zyg, 2022. "Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    17. Shogo Hori & Michihiro Tateyama & Tsuyoshi Shirai & Yoshihiro Kubo & Osamu Saitoh, 2023. "Two single-point mutations in Ankyrin Repeat one drastically change the threshold temperature of TRPV1," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    18. Michael J. Maxwell & Chris Thekkedam & Cedric Lamboley & Yanni K.-Y. Chin & Theo Crawford & Jennifer J. Smith & Junyu Liu & Xinying Jia & Irina Vetter & Derek R. Laver & Bradley S. Launikonis & Angela, 2023. "A bivalent remipede toxin promotes calcium release via ryanodine receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    19. Okwa O Omolade, 2018. "Of Parasites and Their Hosts," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 12(1), pages 8933-8935, December.
    20. Marcos Matamoros & Xue Wen Ng & Joshua B. Brettmann & David W. Piston & Colin G. Nichols, 2023. "Conformational plasticity of NaK2K and TREK2 potassium channel selectivity filters," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-34817-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.