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

  • J Med Chem. 2025 Oct 9;68(19):20377-20388. doi: 10.1021/acs.jmedchem.5c01432.
ChunMei An  1 ,  Wenfeng Cai  2 ,  Peiying Li  1 ,  Jian Li  1 ,  Na Zhao  1 ,  Xu Yang  1 ,  Keqiang Li  1 ,  Ningning Pang  1 ,  Xing Cheng  1 ,  Naiyuan Wang  1 ,  Dong Guo  1 ,  Yizhen Yin  2  3 ,  Xiaochun Xiong  1
Affiliations
  • 1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China.
  • 2. State Key Laboratory of Microbial Technology, Institute of Microbial Technology, Shandong University, Qingdao, Shandong 266237, China.
  • 3. Shandong Research Institute of Industrial Technology, Jinan, Shandong 250101, China.
PMID: 40964801 DOI: 10.1021/acs.jmedchem.5c01432
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.

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