Manchester Pharmacy School, Faculty of Medical and Human Sciences, The University of Manchester , Stopford Building, Oxford Road, Manchester M13 9PT, U.K.
Faculty of Life Sciences, The University of Manchester , AV Hill Building, Oxford Road, Manchester M13 9PT, U.K.
J Med Chem. 2016 Mar 10;59(5):1691-710. doi: 10.1021/acs.jmedchem.5b01091. Epub 2015 Oct 12.
Inflammasomes are high molecular weight complexes that sense and react to injury and infection. Their activation induces caspase-1 activation and release of interleukin-1β, a pro-inflammatory cytokine involved in both acute and chronic inflammatory responses. There is increasing evidence that inflammasomes, particularly the NLRP3 inflammasome, act as guardians against noninfectious material. Inappropriate activation of the NLRP3 inflammasome contributes to the progression of many noncommunicable diseases such as gout, type II diabetes, and Alzheimer's disease. Inhibiting the inflammasome may significantly reduce damaging inflammation and is therefore regarded as a therapeutic target. Currently approved inhibitors of interleukin-1β are rilonacept, canakinumab, and anakinra. However, these proteins do not possess ideal pharmacokinetic properties and are unlikely to easily cross the blood-brain barrier. Because inflammation can contribute to neurological disorders, this review focuses on the development of small-molecule inhibitors of the NLRP3 inflammasome.
炎症小体是一种高分子量复合物，能够感知和应对损伤和感染。它们的激活诱导半胱天冬酶-1 的激活和白细胞介素-1β的释放，白细胞介素-1β是一种参与急性和慢性炎症反应的促炎细胞因子。越来越多的证据表明，炎症小体，特别是 NLRP3 炎症小体，作为非传染性物质的守护者发挥作用。NLRP3 炎症小体的不当激活导致许多非传染性疾病的进展，如痛风、二型糖尿病和阿尔茨海默病。抑制炎症小体可以显著减少破坏性炎症，因此被视为治疗靶点。目前批准的白细胞介素-1β抑制剂有 rilonacept、canakinumab 和 anakinra。然而，这些蛋白质并不具有理想的药代动力学特性，也不太可能轻易穿过血脑屏障。由于炎症可能导致神经紊乱，因此本篇综述重点介绍 NLRP3 炎症小体的小分子抑制剂的开发。
