Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Sci Immunol. 2018 Aug 24;3(26). pii: eaat2738. doi: 10.1126/sciimmunol.aat2738.

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

Author information

1
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
2
Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
3
Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
4
Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
5
Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. dwa4@case.edu.

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.

PMID:
30143556
DOI:
10.1126/sciimmunol.aat2738

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center