Development of a Lactam-Bridged Peptide as Interleukin-11 Antagonist for Renal Fibrosis Treatment

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 DOI:10.1021/acsmedchemlett.6c00034

Xu Yang, Na Zhao, Ranran Zheng, Jian Li, Yujie Wu, Zhenxin Ma, Ningning Pang, Xin Meng, Ruirui Liu, Xiaochun Xiong, Chunmei An

引用次数: 0

Abstract

In recent years, the role of interleukin-11 (IL-11) in renal fibrosis has garnered considerable interest and is regarded as a promising therapeutic target for this condition. Herein, we explored the effects of replacing the oxidation-sensitive thioether moiety with a lactam bridge. By screening linker length and performing further optimization, we developed an analog, 4L6–16. This compound exhibited a high binding affinity for IL-11, with a K_D value of 134 nM, along with enhanced antagonistic activity. Moreover, 4L6–16 demonstrated significant renoprotective effects in both in vitro and in vivo models of renal fibrosis, supporting its potential for further optimization to develop novel IL-11-targeted therapeutic agents.

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内酰胺桥接肽作为肾纤维化治疗白介素-11拮抗剂的研究进展

近年来，白细胞介素-11 （IL-11）在肾纤维化中的作用引起了相当大的兴趣，并被认为是治疗这种疾病的有希望的治疗靶点。在此，我们探索了用内酰胺桥取代氧化敏感的硫醚部分的效果。通过筛选接头长度并进行进一步优化，我们开发了类似物4L6-16。该化合物对IL-11具有较高的结合亲和力，KD值为134 nM，拮抗活性增强。此外，4L6-16在体外和体内肾纤维化模型中均表现出显著的肾保护作用，支持其进一步优化以开发新型il -11靶向治疗剂的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.