The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome activation, but compounds directly and specifically targeting NLRP3 are still not available, so it is unclear whether NLRP3 itself can be targeted to prevent or treat diseases. Here we show that the compound CY-09 specifically blocks NLRP3 inflammasome activation. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation. Importantly, treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes. Furthermore, CY-09 is active ex vivo for monocytes from healthy individuals or synovial fluid cells from patients with gout. Thus, our results provide a selective and direct small-molecule inhibitor for NLRP3 and indicate that NLRP3 can be targeted in vivo to combat NLRP3-driven diseases.

NLRP3炎性小体与多种人类疾病的发病机制有关。已经开发出了几种化合物来抑制NLRP3炎性体的活化，但是仍然没有直接或特异性靶向NLRP3的化合物，因此目前尚不清楚NLRP3本身是否可以预防或治疗疾病。在这里，我们显示化合物CY-09特异性阻断NLRP3炎性体激活。CY-09直接与NLRP3 NACHT域的ATP结合基序结合，并抑制NLRP3 ATPase活性，从而抑制NLRP3炎症小体的组装和激活。重要的是，用CY-09进行的治疗对小鼠冻存素相关性自身炎症综合症（CAPS）和2型糖尿病的模型显示出显着的治疗效果。此外，CY-09对健康个体的单核细胞或痛风患者的滑液细胞具有离体活性。因此，我们的结果为NLRP3提供了选择性和直接的小分子抑制剂，并表明NLRP3可以在体内靶向对抗NLRP3驱动的疾病。