Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.
LifeArc, Accelerator Building, SBC Campus, Stevenage, SG1 2FX, UK.
Sci Rep. 2018 Apr 4;8(1):5667. doi: 10.1038/s41598-018-24029-3.
Inflammation is an established contributor to disease and the NLRP3 inflammasome is emerging as a potential therapeutic target. A number of small molecule inhibitors of the NLRP3 pathway have been described. Here we analysed the most promising of these inhibitor classes side by side to assess relative potency and selectivity for their respective putative targets. Assessed using ASC inflammasome-speck formation, and release of IL-1β, in both human monocyte/macrophage THP1 cells and in primary mouse microglia, we compared the relative potency and selectivity of P2X7 inhibitors, inflammasome inhibitors (diarylsulfonylurea vs. the NBC series), and caspase-1 inhibitors. In doing so we are now able to provide a well characterised small molecule tool kit for interrogating and validating inflammasome-dependent responses with a range of nanomolar potency inhibitors against established points in the inflammasome pathway.
炎症是疾病的一个既定诱因，NLRP3 炎性小体正成为一个有潜力的治疗靶点。已经描述了许多 NLRP3 途径的小分子抑制剂。在这里，我们并排分析了这些抑制剂中最有前途的抑制剂类别，以评估它们各自假定靶点的相对效力和选择性。我们使用 ASC 炎性小体斑点形成和 IL-1β 在人单核细胞/巨噬细胞 THP1 细胞和原代小鼠小神经胶质细胞中的释放来评估，我们比较了 P2X7 抑制剂、炎性小体抑制剂（二芳基磺酰脲与 NBC 系列）和半胱天冬酶-1 抑制剂的相对效力和选择性。通过这样做，我们现在能够提供一个经过充分表征的小分子工具包，用于用一系列对炎症小体途径中的既定靶点具有纳摩尔效力的抑制剂来研究和验证炎症小体依赖性反应。
