Researchers from Harvard Medical School and Boston Children’s Hospital reveal that the FDA-approved drug disulfiram, often used to treat alcoholism, blocks a key gatekeeper protein contributing to inflammation. COVID-19 kills not because of the virus itself, but rather because the body’s immune system overreacts violently in such a way that the consequent severe inflammation leads to dangerous complications and potentially death for what is now tens of thousands who have died in this horrific manner. So could disulfiram represent some way to manage deadly inflammation activated by an overactive immune system?
Recently Alice McCarthy wrote an interesting article for Harvard Medical School’s News and Research online news. She introduced the reader to an interesting, yet obscure body of research centering on a little-known protein called gasdermin D. Highlighted in the May 4 edition of Nature Immunology, two prominent Boston area-based preclinical researchers showcased that mice treated with a drug known as disulfiram failed to develop fatal sepsis as compared with untreated animals. Now why is this relevant? Well as it turns out a gatekeeper protein known as gasdermin D is actually activated as a final common step in inflammatory cell death—also known as pyroptosis. When this occurs, inflammatory cytokines are prevalent in a range of serious conditions including sepsis. For children it turns out sepsis is the leading cause of death worldwide, contributing to 33% of hospitalized deaths.
Hopeful Findings by the Investigators
These recent findings suggest some chance for a therapeutic approach to targeting “runaway inflammation” but because this study was done in mice it is a significant stretch to apply to humans. Co-senior investigator Judy Lieberman, professor of pediatrics at Harvard Medical School and chair of cellular and molecular medicine at Boston Children’s commented, “This research discovery is coincidentally 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 inflammation molecules.”
Hao Wu, the other investigator and professor of biological chemistry and molecular biology in the Blavatnik Institute at HMS and the ASA and Patricia Springer Professor of Structural Biology at Boston’s Children’s Hospital commented “there have not been any bona fide gasdermin D inhibitors.” He continued, “We 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.
Back in 2016, both Lieberman and Wu published a research paper in Nature describing their discovery that gasdermin D forms membrane pores and upon opening, inflammatory molecules spill out of the cell causing what is called pyroptosis. This event also occurs when an invading virus, for example, enters the cell and stimulates inflammation which triggers a flow of events including what is known as pyroptosis—inflammatory cell death. In this situation the cell’s membrane actually explodes, releasing inflammatory molecules such as interleukin-1 an catalyst for fever.
Closing the loop gasdermin D serves as a “gatekeeper of the pathway leading up to pyroptosis and the associated spillage of inflammatory cytokines,” reports Wu.
What is Disulfiram?
Sold under the trad name Antabuse, the drug is used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol. It works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately post drink consumption. The drug has been studied as possible treatment for cancer and latent HIV infection.
Judy Lieberman, professor of pediatrics at Harvard Medical School and chair of cellular and molecular medicine at Boston Children’s Hospital
Hao Wu, PhD, Senior Investigator, Program in Cellular and Molecular Medicine, Boston Children’s Hospital
Call to Action: TrialSite News will delve deeper into any other research teams investigating gasdermin D and Disulfiram.