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

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-09-18 DOI:10.1021/acs.jmedchem.5c01432

ChunMei An, Wenfeng Cai, Peiying Li, Jian Li, Na Zhao, Xu Yang, Keqiang Li, Ningning Pang, Xing Cheng, Naiyuan Wang, Dong Guo, Yizhen Yin, Xiaochun Xiong

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引用次数: 0

摘要

新出现的证据强调了白介素-11 （IL-11）在纤维化疾病中的病理参与。在本研究中，我们通过随机非标准肽整合发现（RaPID）系统鉴定了一种新的肽拮抗剂4L2，该拮抗剂与IL-11具有高结合性，KD值为5.26 nM。此外，基于细胞的实验显示，4L2具有中等拮抗活性，IC50值为22.7±1.9 μM。通过丙氨酸扫描和随后的结构优化，我们开发了一个改进的变体4L2-P13D，其拮抗活性显著增强，IC50值为2.8±0.5 μM。此外，在体外和体内模型中，4L2-P13D显示出显著的肾保护作用。这些发现表明，类似物4L2-P13D代表了开发靶向IL-11治疗肾纤维化的有希望的主要候选药物。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

De Novo Discovery of a Macrocyclic Peptide Antagonist of Interleukin-11 with Antirenal Fibrotic Efficacy

查看原文本刊更多论文

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 K_D 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.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

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.