Targeting the NLRP3 inflammasome for inflammatory disease therapy.

IF 13.9 1区 医学 Q1 PHARMACOLOGY & PHARMACY
Julia Elise Cabral, Anna Wu, Haitian Zhou, Minh Anh Pham, Sophia Lin, Reginald McNulty
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引用次数: 0

Abstract

The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a megadalton complex implicated in numerous inflammation-driven diseases including COVID-19, Alzheimer's disease, and gout. Although past efforts have focused on inhibiting IL-1β downstream of NLRP3 activation using drugs such as canakinumab, no FDA-approved NLRP3-targeted inhibitors are currently available. MCC950, a direct NLRP3 inhibitor, showed promise but exhibited off-target effects. Recent research has focused on optimizing the sulfonylurea-based MCC950 scaffold by leveraging recent structural and medicinal chemistry insights into the NLRP3 nucleotide-binding and oligomerization (NACHT) domain to improve solubility and clinical efficacy. In addition, oxidized DNA (oxDNA) has emerged as a key inflammasome trigger, and molecules targeting the pyrin domain have shown promise in inhibiting NLRP3 activation. This review discusses the role of NLRP3 in inflammation-related diseases, the status of ongoing clinical trials, and emerging small-molecule therapeutics targeting NLRP3.

靶向NLRP3炎性小体用于炎性疾病治疗。
nod样受体pyrin - domain-containing 3 (NLRP3)炎性小体是一种巨达尔顿复合物,与许多炎症驱动的疾病有关,包括COVID-19、阿尔茨海默病和痛风。尽管过去的研究主要集中在使用canakinumab等药物抑制NLRP3激活下游的IL-1β,但目前还没有fda批准的NLRP3靶向抑制剂。MCC950是一种直接的NLRP3抑制剂,显示出良好的前景,但表现出脱靶效应。最近的研究主要集中在优化基于磺脲的MCC950支架,利用最近的结构和药物化学见解到NLRP3核苷酸结合和寡聚化(NACHT)结构域,以提高溶解度和临床疗效。此外,氧化DNA (oxDNA)已成为炎症小体的关键触发因素,靶向pyrin结构域的分子已显示出抑制NLRP3激活的希望。本文综述了NLRP3在炎症相关疾病中的作用,正在进行的临床试验的现状,以及针对NLRP3的新小分子治疗方法。
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
CiteScore
23.90
自引率
0.70%
发文量
132
审稿时长
6-12 weeks
期刊介绍: Trends in Pharmacological Sciences (TIPS) is a monthly peer-reviewed reviews journal that focuses on a wide range of topics in pharmacology, pharmacy, pharmaceutics, and toxicology. Launched in 1979, TIPS publishes concise articles discussing the latest advancements in pharmacology and therapeutics research. The journal encourages submissions that align with its core themes while also being open to articles on the biopharma regulatory landscape, science policy and regulation, and bioethics. Each issue of TIPS provides a platform for experts to share their insights and perspectives on the most exciting developments in the field. Through rigorous peer review, the journal ensures the quality and reliability of published articles. Authors are invited to contribute articles that contribute to the understanding of pharmacology and its applications in various domains. Whether it's exploring innovative drug therapies or discussing the ethical considerations of pharmaceutical research, TIPS provides a valuable resource for researchers, practitioners, and policymakers in the pharmacological sciences.
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