环肽抑制剂在肠道中特异性破坏fxr -辅激活物相互作用的发展作为一种新的治疗MASH的策略。

Life metabolism Pub Date : 2025-02-08 eCollection Date: 2025-04-01 DOI:10.1093/lifemeta/loaf004
Yazhou Li, Tingying Jiao, Xi Cheng, Lu Liu, Mengjiao Zhang, Jian Li, Jue Wang, Shulei Hu, Cuina Li, Tao Yu, Yameng Liu, Yangtai Li, Yu Zhang, Chuying Sun, Jina Sun, Jiang Wang, Cen Xie, Hong Liu
{"title":"环肽抑制剂在肠道中特异性破坏fxr -辅激活物相互作用的发展作为一种新的治疗MASH的策略。","authors":"Yazhou Li, Tingying Jiao, Xi Cheng, Lu Liu, Mengjiao Zhang, Jian Li, Jue Wang, Shulei Hu, Cuina Li, Tao Yu, Yameng Liu, Yangtai Li, Yu Zhang, Chuying Sun, Jina Sun, Jiang Wang, Cen Xie, Hong Liu","doi":"10.1093/lifemeta/loaf004","DOIUrl":null,"url":null,"abstract":"<p><p>Intestinal farnesoid X receptor (FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). All the reported FXR antagonists target to the ligand-binding pocket (LBP) of the receptor, whereas antagonist acting on the non-LBP site of nuclear receptor (NR) is conceived as a promising strategy to discover novel FXR antagonist. Here, we have postulated the hypothesis of antagonizing FXR by disrupting the interaction between FXR and coactivators, and have successfully developed a series of macrocyclic peptides as FXR antagonists based on this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity of FXR, but also demonstrates a high degree of selectivity towards other NRs. Moreover, cyclopeptide DC646 has high potential therapeutic benefit for the treatment of MASH in an intestinal FXR-dependent manner, along with a commendable safety profile. Mechanistically, distinct from other known FXR antagonists, cyclopeptide DC646 specifically binds to the coactivator binding site of FXR, which can block the coactivator recruitment, reducing the circulation of intestine-derived ceramides to the liver, and promoting the release of glucagon-like peptide-1 (GLP-1). Overall, we identify a novel cyclopeptide that targets FXR-coactivator interaction, paving the way for a new approach to treating MASH with FXR antagonists.</p>","PeriodicalId":74074,"journal":{"name":"Life metabolism","volume":"4 2","pages":"loaf004"},"PeriodicalIF":0.0000,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11992618/pdf/","citationCount":"0","resultStr":"{\"title\":\"Development of cyclopeptide inhibitors specifically disrupting FXR-coactivator interaction in the intestine as a novel therapeutic strategy for MASH.\",\"authors\":\"Yazhou Li, Tingying Jiao, Xi Cheng, Lu Liu, Mengjiao Zhang, Jian Li, Jue Wang, Shulei Hu, Cuina Li, Tao Yu, Yameng Liu, Yangtai Li, Yu Zhang, Chuying Sun, Jina Sun, Jiang Wang, Cen Xie, Hong Liu\",\"doi\":\"10.1093/lifemeta/loaf004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Intestinal farnesoid X receptor (FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). All the reported FXR antagonists target to the ligand-binding pocket (LBP) of the receptor, whereas antagonist acting on the non-LBP site of nuclear receptor (NR) is conceived as a promising strategy to discover novel FXR antagonist. Here, we have postulated the hypothesis of antagonizing FXR by disrupting the interaction between FXR and coactivators, and have successfully developed a series of macrocyclic peptides as FXR antagonists based on this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity of FXR, but also demonstrates a high degree of selectivity towards other NRs. Moreover, cyclopeptide DC646 has high potential therapeutic benefit for the treatment of MASH in an intestinal FXR-dependent manner, along with a commendable safety profile. Mechanistically, distinct from other known FXR antagonists, cyclopeptide DC646 specifically binds to the coactivator binding site of FXR, which can block the coactivator recruitment, reducing the circulation of intestine-derived ceramides to the liver, and promoting the release of glucagon-like peptide-1 (GLP-1). Overall, we identify a novel cyclopeptide that targets FXR-coactivator interaction, paving the way for a new approach to treating MASH with FXR antagonists.</p>\",\"PeriodicalId\":74074,\"journal\":{\"name\":\"Life metabolism\",\"volume\":\"4 2\",\"pages\":\"loaf004\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-02-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11992618/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Life metabolism\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/lifemeta/loaf004\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/4/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life metabolism","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/lifemeta/loaf004","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

摘要

肠法内甾体X受体(FXR)拮抗剂已被证明在改善代谢性疾病方面有效,特别是对代谢功能障碍相关脂肪性肝炎(MASH)的治疗。已报道的FXR拮抗剂均靶向受体的配体结合袋(LBP),而作用于核受体的非LBP位点(NR)的拮抗剂被认为是发现新型FXR拮抗剂的有希望的策略。本研究提出了通过破坏FXR与辅激活剂之间的相互作用来拮抗FXR的假设,并在此前提下成功开发了一系列作为FXR拮抗剂的大环肽。环肽DC646不仅对FXR具有较强的抑制活性,而且对其他rna也有较高的选择性。此外,环肽DC646在肠道fxr依赖性治疗MASH方面具有很高的潜在治疗效益,同时具有值得称道的安全性。机制上,与其他已知的FXR拮抗剂不同,环肽DC646特异性结合FXR的辅激活剂结合位点,可阻断辅激活剂的募集,减少肠源性神经酰胺向肝脏的循环,促进胰高血糖素样肽-1 (GLP-1)的释放。总之,我们发现了一种新的环肽靶向FXR-辅激活剂相互作用,为FXR拮抗剂治疗MASH的新方法铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Development of cyclopeptide inhibitors specifically disrupting FXR-coactivator interaction in the intestine as a novel therapeutic strategy for MASH.

Intestinal farnesoid X receptor (FXR) antagonists have been proven to be efficacious in ameliorating metabolic diseases, particularly for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). All the reported FXR antagonists target to the ligand-binding pocket (LBP) of the receptor, whereas antagonist acting on the non-LBP site of nuclear receptor (NR) is conceived as a promising strategy to discover novel FXR antagonist. Here, we have postulated the hypothesis of antagonizing FXR by disrupting the interaction between FXR and coactivators, and have successfully developed a series of macrocyclic peptides as FXR antagonists based on this premise. The cyclopeptide DC646 not only exhibits potent inhibitory activity of FXR, but also demonstrates a high degree of selectivity towards other NRs. Moreover, cyclopeptide DC646 has high potential therapeutic benefit for the treatment of MASH in an intestinal FXR-dependent manner, along with a commendable safety profile. Mechanistically, distinct from other known FXR antagonists, cyclopeptide DC646 specifically binds to the coactivator binding site of FXR, which can block the coactivator recruitment, reducing the circulation of intestine-derived ceramides to the liver, and promoting the release of glucagon-like peptide-1 (GLP-1). Overall, we identify a novel cyclopeptide that targets FXR-coactivator interaction, paving the way for a new approach to treating MASH with FXR antagonists.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
1.10
自引率
0.00%
发文量
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信