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 <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.

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Publication Details

Journal
Journal of Medicinal Chemistry
Published
2025-09-18
DOI
https://doi.org/10.1021/acs.jmedchem.5c01432
Citations
2
Primary Topic
Toxin Mechanisms and Immunotoxins
Type
article
Field-Weighted Citation Impact
1.59
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article

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

Yizhen Yin, Wang Nai-yuan, Peiying Li, Yang Xu et al.
2 citations
Journal of Medicinal Chemistry
Toxin Mechanisms and Immunotoxins
1.59
article

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

Yizhen Yin, Wang Nai-yuan, Peiying Li, Yang Xu, Wenfeng Cai, Xiaochun Xiong, Keqiang Li, Jian Li, Chunmei An, Na Zhao, Dong Guo, Xing Cheng, Ningning Pang
article en
2 citations

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 <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.

Journal of Medicinal ChemistryVol. 68(19)
Shandong University (CN), Xuzhou Medical College (CN), Institute of Microbial Technology (IN)
Openalex Percentile: Top 15%
Toxin Mechanisms and Immunotoxins
1.59
DOISourceOpenAlex
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De Novo Discovery of a Macrocyclic Peptide Antagonist of Interleukin-11 with Antirenal Fibrotic Efficacy — Yizhen Yin, Wang Nai-yuan, et al. · Journal of Medicinal Chemistry (2025) | TGRS Research Map | TGRS