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

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 reco...

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Autores principales: Zhang, Heng, Lin, Jia-Jia, Xie, Ya-Kai, Song, Xiu-Zu, Sun, Jia-Yi, Zhang, Bei-Lei, Qi, Yun-Kun, Xu, Zhen-Zhong, Yang, Fan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810691/
https://www.ncbi.nlm.nih.gov/pubmed/36596769
http://dx.doi.org/10.1038/s41467-022-34817-1
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author Zhang, Heng
Lin, Jia-Jia
Xie, Ya-Kai
Song, Xiu-Zu
Sun, Jia-Yi
Zhang, Bei-Lei
Qi, Yun-Kun
Xu, Zhen-Zhong
Yang, Fan
author_facet Zhang, Heng
Lin, Jia-Jia
Xie, Ya-Kai
Song, Xiu-Zu
Sun, Jia-Yi
Zhang, Bei-Lei
Qi, Yun-Kun
Xu, Zhen-Zhong
Yang, Fan
author_sort Zhang, Heng
collection PubMed
description 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.
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spelling pubmed-98106912023-01-05 Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia Zhang, Heng Lin, Jia-Jia Xie, Ya-Kai Song, Xiu-Zu Sun, Jia-Yi Zhang, Bei-Lei Qi, Yun-Kun Xu, Zhen-Zhong Yang, Fan Nat Commun Article 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. Nature Publishing Group UK 2023-01-03 /pmc/articles/PMC9810691/ /pubmed/36596769 http://dx.doi.org/10.1038/s41467-022-34817-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Heng
Lin, Jia-Jia
Xie, Ya-Kai
Song, Xiu-Zu
Sun, Jia-Yi
Zhang, Bei-Lei
Qi, Yun-Kun
Xu, Zhen-Zhong
Yang, Fan
Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia
title Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia
title_full Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia
title_fullStr Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia
title_full_unstemmed Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia
title_short Structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of TRPV1 for long-lasting analgesia
title_sort structure-guided peptide engineering of a positive allosteric modulator targeting the outer pore of trpv1 for long-lasting analgesia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9810691/
https://www.ncbi.nlm.nih.gov/pubmed/36596769
http://dx.doi.org/10.1038/s41467-022-34817-1
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