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Gasdermin D inhibitor protects against sepsis

  1. Sarah Crunkhorn
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Gasdermin D (GSDMD) is the final common effector of inflammasome activation, forming membrane pores to enable pro-inflammatory cytokine release and pyroptosis. Inhibiting GSDMD, therefore, represents a promising approach to treat inflammatory disorders. Through a high-throughput screen, Hu et al. identify disulfiram (used to treat alcohol addiction) as a potent inhibitor of GSDMD pore formation. In cells, disulfiram inhibited cytokine release and prevented pyroptosis. In mice, the drug protected from lethal lipopolysaccharide-induced septic shock. Mechanistically, disulfiram covalently modified Cys191 of human GSDMD to block pore formation.

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Nature Reviews Drug Discovery 19, 388 (2020)

doi: https://doi.org/10.1038/d41573-020-00084-2

References

  1. Hu, J. J. et al. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat. Immunol. https://doi.org/10.1038/s41590-020-0669-6 (2020)

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