Researchers from Harvard Medical School have shown that Disulfiram, an FDA-approved pharmacologic inhibitor of the enzyme that metabolizes ethanol, could be re-purposed from treating alcohol addiction to preventing life-threatening inflammation.
The immune system can become activated when intracellular protein complexes known as inflammasomes induce the release of signaling molecules (“cytokines”) from damaged or infected cells. The process involves both the induction of pro-inflammatory cytokine production and the formation of cell membrane pores that enable the transit of cytokines out of the cells.
The scientists discovered that Disulfiram blocks the assembly of gasdermin D (GSDMD) proteins, which constitute the building blocks of the pores, to effectively prevent cytokine release and reduce inflammation. Their findings could influence the treatment of multiple human diseases.
“Inflammation is responsible for or exacerbates many difficult to treat human diseases, including sepsis, atherosclerosis, autoimmune diseases, Type II diabetes, gout and Alzheimer’s disease,” stated co-senior author Dr. Judy Lieberman, MD, PhD.
“Gasdermin D was recently identified as the gatekeeper for inflammatory cell death (called pyroptosis for “fiery” death) triggered when cytosolic sensors in sentinel immune cells recognize invasive infections or other signs of danger to the cell. Gasdermin gets cleaved when danger or infection is sensed and then forms pores on cell membranes, which damage them, causing the cell to die and leak some of its contents, which cause inflammation. Gasdermin D pores are also required to release inflammatory cytokines that cause fever and inflammation.”
“Release of inflammatory cytokines (called cytokine release syndrome or cytokine storm) is also thought to be at the root of pneumonia and acute respiratory distress syndrome in COVID-19 patients who deteriorate. We hypothesized that inhibiting gasdermin D could reduce inflammation and treat inflammation-related diseases. We therefore did a small molecule drug screen to identify compounds that could inhibit gasdermin D from making membrane pores.”
“We used liposomes that contain lipids to which activated gasdermin D binds and loaded them with a dye and screened for compounds that blocked leakage of the dye from liposomes. The top hit was an FDA-approved drug (disulfiram or Antabuse) used for 70 years to treat alcohol dependence. We found that disulfiram blocked pyroptosis activated in multiple ways in vitro and also blocked cytokine release and improved survival in a mouse sepsis model.”
“This is the first specific and potent inhibitor of gasdermin D identified. Inflammation is a potent contributor to many serious diseases, including sepsis, which is the leading cause of death of children worldwide and contributes to the deaths of about a third of hospitalized patients, for which there is no effective specific treatment other than antibiotics and supportive care. Disulfiram might also be a cheap well-tolerated drug that could be effective for patients infected with SARS-CoV2 at risk for serious respiratory disease,” Dr. Lieberman continued.
The study, “FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation,” was published in the journal Nature Immunology. Dr. Lieberman and Dr. Hao Wu, PhD, were the senior authors.
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Moving forwards, the team plans to evaluate the inflammation-reducing properties of the drug in other contexts and possibly even initiate a clinical trial. Disulfiram is regarded as safe for use in humans and already approved by the United States Food and Drug Administration.
“We plan to test disulfiram in more disease models, including in vitro SARS-CoV-2 infection and in mouse models of autoinflammatory disease and infection. We would like to see some clinical studies. We are working with a biotech company to develop other inhibitors of gasdermin D,” commented Dr. Lieberman.
“Understanding the molecular basis for inflammatory death and a key gatekeeper protein that controls it provides a new way to inhibit inflammation that could be a powerful therapeutic.”