In a new study, researchers discovered that disulfiram, an FDA-approved drug commonly used for treating alcoholism, blocks a key gatekeeper protein involved in inflammation.
Activation of that protein, gasdermin D, is the final common step in the process of inflammatory cell death, or pyroptosis, and the resulting release of inflammatory cytokines seen in many serious conditions including sepsis.
Animals treated with disulfiram did not develop fatal sepsis compared with untreated animals.
This research discovery is very timely today because most people think that the clinical deterioration of COVID-19 patients is mediated by a cytokine storm or excessive release of inflammatory molecules.
The research was conducted by a team at Boston Children’s Hospital.
When an invading virus or bacteria enter a cell, it triggers inflammation unleashing a cascade of events. One key event is called pyroptosis, or fiery or inflammatory cell death.
Too much inflammation contributes to human diseases, including sepsis, inflammatory bowel disease, gout, type II diabetes, cardiovascular disease, Alzheimer’s disease, and is responsible for rare inflammatory genetic diseases.
Previously, the team had discovered that gasdermin D forms membrane pores. When these pores open, inflammatory molecules spill out of the cell causing pyroptosis.
Even though there has been a lot of interest, there have not been any bona fide gasdermin D inhibitors.
In the study, the team screened thousands of compounds and found that the one that worked best—disulfiram—is already on the market, is inexpensive, has a 70-year history of drug safety, and could be repurposed pretty quickly.
They hope that with this new discovery— inhibiting gasdermin D that is in a critical location in the inflammatory pathway— could actually offer a therapy that might work.
The team is now looking to apply these findings to COVID-19. The ultimate goal is to start a clinical trial with disulfiram in COVID-19 patients.
One author of the study is Judy Lieberman, MD, Ph.D.
The study is published in Nature Immunology.
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