Research ArticleCELL DEATH

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

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Science Immunology  24 Aug 2018:
Vol. 3, Issue 26, eaat2738
DOI: 10.1126/sciimmunol.aat2738

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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.

Abstract

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.

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