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

Joseph K Rathkey; Junjie Zhao; Zhonghua Liu; Yinghua Chen; Jie Yang; Hannah C Kondolf; Bryan L Benson; Steven M Chirieleison; Alex Y Huang; George R Dubyak; Tsan S Xiao; Xiaoxia Li; Derek W Abbott

doi:10.1126/sciimmunol.aat2738

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

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

Authors

Affiliations

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. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acrylamides / pharmacology*
Acrylamides / therapeutic use
Animals
Apoptosis Regulatory Proteins / antagonists & inhibitors*
Apoptosis Regulatory Proteins / physiology
Cytokines / genetics
Female
HEK293 Cells
Humans
Intracellular Signaling Peptides and Proteins
Lipopolysaccharides
Macrophages / drug effects
Mice, Inbred C57BL
Monocytes / drug effects
NLR Family, Pyrin Domain-Containing 3 Protein / physiology
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / physiology
Phosphate-Binding Proteins
Pyrin / physiology
Pyroptosis / drug effects*
Salmonella Infections / drug therapy
Salmonella Infections / immunology
Salmonella typhimurium
Sepsis / drug therapy
Sepsis / immunology
Sulfonamides / pharmacology*
Sulfonamides / therapeutic use
THP-1 Cells

Substances

Acrylamides
Apoptosis Regulatory Proteins
Cytokines
GSDMD protein, human
Gsdmd protein, mouse
Intracellular Signaling Peptides and Proteins
Lipopolysaccharides
N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide
NLR Family, Pyrin Domain-Containing 3 Protein
Neoplasm Proteins
Phosphate-Binding Proteins
Pyrin
Sulfonamides

Abstract

Publication types

MeSH terms

Substances

Grants and funding