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小分子靶向 NLRP3 炎性小体抑制的研究进展与展望

Recent Progress and Prospects of Small Molecules for NLRP3 Inflammasome Inhibition.

机构信息

Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.

Laboratory of Metabolomics and Drug-Induced Liver Injury, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.

出版信息

J Med Chem. 2023 Nov 9;66(21):14447-14473. doi: 10.1021/acs.jmedchem.3c01370. Epub 2023 Oct 25.

Abstract

NLRP3 inflammasome is a multiprotein complex involved in host immune response─which exerts various biological effects by mediating the maturation and secretion of IL-1β and IL-18─and pyroptosis. However, its aberrant activation could cause amplification of inflammatory effects, thereby triggering a range of ailments, including Alzheimer's disease, Parkinson's disease, rheumatoid arthritis, gout, type 2 diabetes mellitus, and cancer. For the past few years, as an attractive anti-inflammatory target, NLRP3-targeting small-molecule inhibitors have been widely reported by both the academic and the industrial communities. In order to deeply understand the advancement of NLRP3 inflammasome inhibitors, we provide comprehensive insights and commentary on drugs currently under clinical investigation, as well as other NLRP3 inflammasome inhibitors from a chemical structure point of view, with an aim to provide new insights for the further development of clinical drugs for NLRP3 inflammasome-mediated diseases.

摘要

NLRP3 炎性小体是一种多蛋白复合物,参与宿主免疫反应─通过调节 IL-1β 和 IL-18 的成熟和分泌以及细胞焦亡来发挥多种生物学效应。然而,其异常激活会导致炎症效应的放大,从而引发一系列疾病,包括阿尔茨海默病、帕金森病、类风湿性关节炎、痛风、2 型糖尿病和癌症。在过去的几年中,作为一种有吸引力的抗炎靶点,NLRP3 靶向小分子抑制剂受到学术界和工业界的广泛关注。为了深入了解 NLRP3 炎性小体抑制剂的进展,我们从化学结构的角度对目前处于临床研究阶段的药物以及其他 NLRP3 炎性小体抑制剂进行了全面的分析和评论,以期为 NLRP3 炎性小体介导的疾病的临床药物的进一步开发提供新的思路。

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