IL-23诱导矫形袋的鉴定:非生物靶向治疗的新途径。

IF 3.5 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Fabien C Lecomte, Jeremiah S Joseph, Jacek Stalewski, Qingliang Shen, Eric Arnoult, Vandana Sridhar, Mengjie Liu, Yingxia Hu, Jovylyn Gatchalian Gasendo, Hagit Ben Arie, Nurit Keinan, Liraz Keidar, Israel Aviv, Emil Ruvinov, Julia Grandjean, Paulo Roberto Dores-Silva, Annie Mak, Buyung Santoso, Suzie Kim, Vikram Shende, Walter J Wever, Tara Mirzadegan, Zhaoning Zhu, Bryan Fuchs, Philippe Pinton, Rose Szabady
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引用次数: 0

摘要

白细胞介素23 (il - 23)是自身免疫性炎症病理的关键驱动因素,已成功地被治疗性抗体靶向治疗银屑病和溃疡性结肠炎。确定il - 23信号传导的小分子抑制剂对药物开发具有潜在的兴趣。我们报告在IL23p19亚基上鉴定了一个诱导拟合的正交结合口袋,可能适合于小分子抑制。利用x射线晶体学确定il - 23异源二聚体与抑制肽23-446结合时的结构,并确认肽与il - 23受体(IL23R)界面位置的il - 23p19亚基结合。然后,我们应用基于结构的设计来修饰肽23-446。这一过程包括确定抑制活性的关键残基,并生成结构-活性关系优化的肽,这些肽对IL-23具有低纳摩尔亲和力,并具有相应的抑制IL-23R结合的能力。这些优化后的肽本身就有可能成为潜在的治疗候选者,也可能作为进一步发现的有价值的起点。这些肽中最有效的肽被用于开发荧光偏振探针和设计高通量筛选试验,并通过使用小片段化合物文库进行中试筛选验证。这种筛选策略有可能支持发现与正位口袋结合的肽或小分子,从而阻断IL-23R相互作用和下游信号传导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of an Induced Orthosteric Pocket in IL-23: A New Avenue for Non-biological Therapeutic Targeting.

Interleukin 23 (IL23) is a key driver of autoimmune inflammatory pathology and has been successfully targeted by therapeutic antibodies for the treatment of psoriasis and ulcerative colitis. Identifying small-molecule inhibitors of IL23 signaling is of potential interest for drug development. We report the identification of an induced-fit orthosteric binding pocket on the IL23p19 subunit that may be suitable for small-molecule inhibition. X-ray crystallography was used to determine the structure of the IL23 heterodimer when bound to inhibitory peptide 23-446 and to confirm peptide binding to the IL23p19 subunit at the location of its interface with the IL23 receptor (IL23R). We then applied structure-based design to modify peptide 23-446. This process involved identifying key residues responsible for inhibitory activity and generating structure-activity relationship-optimized peptides with low nanomolar affinity for IL-23 and corresponding inhibitory potency against IL-23R binding. These optimized peptides show promise as potential therapeutic candidates in their own right and may also serve as valuable starting points for further discovery. The most potent of these peptides was used to develop a fluorescence polarization probe and to design a high-throughput screening assay, which was validated through a pilot screen using a small fragment-based compound library. This screening strategy has the potential to support the discovery of peptides or small molecules that bind to the orthosteric pocket, thereby blocking the IL-23R interaction and downstream signaling.

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来源期刊
ACS Chemical Biology
ACS Chemical Biology 生物-生化与分子生物学
CiteScore
7.50
自引率
5.00%
发文量
353
审稿时长
3.3 months
期刊介绍: ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.
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