n-(4-(n-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide and Sepsis

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.

Topics: Acrylamides; Animals; Apoptosis Regulatory Proteins; Cytokines; Female; HEK293 Cells; Humans; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Macrophages; Mice, Inbred C57BL; Monocytes; Neoplasm Proteins; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphate-Binding Proteins; Pyrin; Pyroptosis; Salmonella Infections; Salmonella typhimurium; Sepsis; Sulfonamides; THP-1 Cells