Joseph K. Rathkey, Junjie Zhao, Zhonghua Liu
Aug 3, 2018
Citations
18
Influential Citations
344
Citations
Quality indicators
Journal
Science Immunology
Abstract
Necrosulfonamide inhibits pyroptosis through direct inhibition of gasdermin D. Targeting gasdermin D Gasdermin D (GSDMD) is a key downstream effector in inflammasome-driven, caspase-1–dependent and lipopolysaccharide-driven, caspase-11–dependent pyroptosis. Upon activation and caspase-dependent proteolytic cleavage, GSDMD oligomerizes to form pores that facilitate pyroptotic cell death. Here, Rathkey et al. report necrosulfonamide (NSA) to be an inhibitor of GSDMD and GSDMD-mediated pyroptosis. They propose that NSA binds to cysteine 191 and inhibits the oligomerization of GSDMD dimers. NSA could be used as a template to develop more potent inhibitors of GSDMD, an important goal for the treatment of septic shock. In the same issue, Sollberger et al. independently report a pyrazolo-oxazepine scaffold–based molecule to be an inhibitor of GSDMD. 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.