{"title":"一种具有抗肾纤维化疗效的白介素-11大环肽拮抗剂的新发现","authors":"ChunMei An, , , Wenfeng Cai, , , Peiying Li, , , Jian Li, , , Na Zhao, , , Xu Yang, , , Keqiang Li, , , Ningning Pang, , , Xing Cheng, , , Naiyuan Wang, , , Dong Guo*, , , Yizhen Yin*, , and , Xiaochun Xiong*, ","doi":"10.1021/acs.jmedchem.5c01432","DOIUrl":null,"url":null,"abstract":"<p >Emerging evidence has highlighted the pathological involvement of interleukin-11 (IL-11) in fibrotic disorders. In this study, we identified a novel peptide antagonist <b>4L2</b> through the random nonstandard peptide integrated discovery (RaPID) system, which exhibits a high binding toward IL-11, with a <i>K</i><sub>D</sub> value of 5.26 nM. Additionally, cell-based assays revealed that <b>4L2</b> displays a moderate antagonistic activity, with an IC<sub>50</sub> value of 22.7 ± 1.9 μM. Through performing alanine scanning and subsequent structural optimization, we developed an improved variant, <b>4L2-P13D</b>, which showed significantly enhanced antagonistic activity, with an IC<sub>50</sub> value of 2.8 ± 0.5 μM. Furthermore, <b>4L2-P13D</b> demonstrated the significant renoprotective effects in <i>in vitro</i> and <i>in vivo</i> models. These findings indicate that the analogue <b>4L2-P13D</b> represents a promising lead candidate for developing targeted IL-11 therapeutics against renal fibrosis.</p>","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":"68 19","pages":"20377–20388"},"PeriodicalIF":6.8000,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"De Novo Discovery of a Macrocyclic Peptide Antagonist of Interleukin-11 with Antirenal Fibrotic Efficacy\",\"authors\":\"ChunMei An, , , Wenfeng Cai, , , Peiying Li, , , Jian Li, , , Na Zhao, , , Xu Yang, , , Keqiang Li, , , Ningning Pang, , , Xing Cheng, , , Naiyuan Wang, , , Dong Guo*, , , Yizhen Yin*, , and , Xiaochun Xiong*, \",\"doi\":\"10.1021/acs.jmedchem.5c01432\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >Emerging evidence has highlighted the pathological involvement of interleukin-11 (IL-11) in fibrotic disorders. In this study, we identified a novel peptide antagonist <b>4L2</b> through the random nonstandard peptide integrated discovery (RaPID) system, which exhibits a high binding toward IL-11, with a <i>K</i><sub>D</sub> value of 5.26 nM. Additionally, cell-based assays revealed that <b>4L2</b> displays a moderate antagonistic activity, with an IC<sub>50</sub> value of 22.7 ± 1.9 μM. Through performing alanine scanning and subsequent structural optimization, we developed an improved variant, <b>4L2-P13D</b>, which showed significantly enhanced antagonistic activity, with an IC<sub>50</sub> value of 2.8 ± 0.5 μM. Furthermore, <b>4L2-P13D</b> demonstrated the significant renoprotective effects in <i>in vitro</i> and <i>in vivo</i> models. These findings indicate that the analogue <b>4L2-P13D</b> represents a promising lead candidate for developing targeted IL-11 therapeutics against renal fibrosis.</p>\",\"PeriodicalId\":46,\"journal\":{\"name\":\"Journal of Medicinal Chemistry\",\"volume\":\"68 19\",\"pages\":\"20377–20388\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-09-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01432\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.jmedchem.5c01432","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
De Novo Discovery of a Macrocyclic Peptide Antagonist of Interleukin-11 with Antirenal Fibrotic Efficacy
Emerging evidence has highlighted the pathological involvement of interleukin-11 (IL-11) in fibrotic disorders. In this study, we identified a novel peptide antagonist 4L2 through the random nonstandard peptide integrated discovery (RaPID) system, which exhibits a high binding toward IL-11, with a KD value of 5.26 nM. Additionally, cell-based assays revealed that 4L2 displays a moderate antagonistic activity, with an IC50 value of 22.7 ± 1.9 μM. Through performing alanine scanning and subsequent structural optimization, we developed an improved variant, 4L2-P13D, which showed significantly enhanced antagonistic activity, with an IC50 value of 2.8 ± 0.5 μM. Furthermore, 4L2-P13D demonstrated the significant renoprotective effects in in vitro and in vivo models. These findings indicate that the analogue 4L2-P13D represents a promising lead candidate for developing targeted IL-11 therapeutics against renal fibrosis.
期刊介绍：
The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents.
The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.
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