Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis

作者：Joseph K. Rathkey, Junjie Zhao, Zhonghua Liu, Yinghua Chen, Jie Yang, Hannah Kondolf, Bryan L. Benson, Steven M. Chirieleison, Alex Y. Huang, George Dubyak, Tsan Sam Xiao, Xiaoxia Li, Derek W. Abbott · 发表于：Science Immunology · 年份：2018 · DOI：10.1126/sciimmunol.aat2738 · 被引用次数：616 · 研究领域：Inflammasome and immune disorders、Gout, Hyperuricemia, Uric Acid、Autoimmune and Inflammatory Disorders Research

Dysregulation of inflammatory cell death is a key driver of many inflammatory diseases. Pyroptosis, a highly inflammatory form of cell death, uses intracellularly generated pores to disrupt electrolyte homeostasis and execute cell death. Gasdermin D, the pore-forming effector protein of pyroptosis, coordinates membrane lysis and the release of highly inflammatory molecules, such as interleukin-1β, which potentiate the overactivation of the innate immune response. However, to date, there is no pharmacologic mechanism to disrupt pyroptosis. Here, we identify necrosulfonamide as a direct chemical inhibitor of gasdermin D, the pyroptotic pore-forming protein, which binds directly to gasdermin D to inhibit pyroptosis. Pharmacologic inhibition of pyroptotic cell death by necrosulfonamide is efficacious in sepsis models and suggests that gasdermin D inhibitors may be efficacious clinically in inflammatory diseases.