De Novo Discoveryof a Macrocyclic Peptide Antagonistof Interleukin-11 with Antirenal Fibrotic Efficacy

作者：Chunmei An, Wenfeng Cai, Peiying Li, Jian Li, Na Zhao, Yang Xu, Keqiang Li, Ningning Pang, Xing Cheng, Naiyuan Wang, Dong Guo, Yizhen Yin, Xiaochun Xiong · 发表于：Journal of Medicinal Chemistry · 年份：2025 · DOI：10.1021/acs.jmedchem.5c01432 · 被引用次数：3 · 研究领域：Toxin Mechanisms and Immunotoxins、Cytokine Signaling Pathways and Interactions、Transgenic Plants and Applications

Abstract 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.