Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Medicinal Chemistry, College of Pharmaceutical Sciences, Soochow University, 1 Wenjing Road, Suzhou 215123, China.
Curr Med Chem. 2021;28(3):569-582. doi: 10.2174/0929867327666200123093544.
Inflammation is the body's immune system's fast coordinating response to irritants caused by pathogens, external injuries, and chemical or radiation effects. The nucleotidebinding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. The dysfunction of NLRP3 inflammasome contributes to various pathogeneses of complex diseases, such as uncontrolled infection, autoimmune diseases, neurodegenerative diseases, and metabolic disorders. This review describes recent progress on the discovery of NLRP3 inflammasome inhibitors and their therapeutic potential.
Based on the mechanism of NLRP3 activation, several types of NLRP3 inhibitors are described and summarized according to their origins, structures, bioactivity, and mechanism of action. Structure-Activity Relationship (SAR) is also listed for different scaffolds, as well as effective pharmacophore.
Over one-hundred papers were included in the review. The development of NLRP3 inhibitors has been described from the earliest glyburide in 2001 to the latest progress in 2019. Several series of inhibitors have been categorized, such as JC-series based on glyburide and BC-series based on 2APB. Many other small molecules such as NLRP3 inhibitors are also listed. SAR, application in related therapeutic models, and five different action mechanisms are described.
The findings of this review confirmed the importance of developing NLRP3 inflammasome inhibitors. Various NLRP3 inhibitors have been discovered as effective therapeutic treatments for multiple diseases, such as type II diabetes, experimental autoimmune encephalomyelitis, stressrelated mood disorders, etc. The development of a full range of NLRP3 inflammasome inhibitors is still at its foundational phase. We are looking forward to the identification of inhibitory agents that provide the most potent therapeutic strategies and efficiently treat NLRP3 inflammasome-related inflammatory diseases.
炎症是机体免疫系统对病原体、外伤和化学或辐射效应等刺激物的快速协调反应。核苷酸结合寡聚化结构域样受体家族富含pyrin 结构域蛋白 3（NLRP3）炎性小体是先天免疫系统的关键组成部分。NLRP3 炎性小体的功能障碍与各种复杂疾病的发病机制有关，如失控性感染、自身免疫性疾病、神经退行性疾病和代谢紊乱。本综述描述了 NLRP3 炎性小体抑制剂的发现及其治疗潜力的最新进展。
根据 NLRP3 激活的机制，根据其来源、结构、生物活性和作用机制，对几种 NLRP3 抑制剂进行了描述和总结。还列出了不同支架的结构-活性关系（SAR）以及有效的药效团。
本综述共纳入 100 余篇文献。描述了从 2001 年最早的格列本脲到 2019 年的最新进展。已经对几类抑制剂进行了分类，如基于格列本脲的 JC 系列和基于 2APB 的 BC 系列。还列出了许多其他小分子抑制剂，如 NLRP3 抑制剂。描述了 SAR、在相关治疗模型中的应用以及五种不同的作用机制。
本综述的研究结果证实了开发 NLRP3 炎性小体抑制剂的重要性。已经发现了各种 NLRP3 抑制剂，作为多种疾病的有效治疗方法，如 2 型糖尿病、实验性自身免疫性脑脊髓炎、应激相关情绪障碍等。NLRP3 炎性小体抑制剂的全面开发仍处于基础阶段。我们期待发现具有最强治疗策略并能有效治疗 NLRP3 炎性小体相关炎症性疾病的抑制剂。
