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Source: Covid-19 Research  May 26, 2020  2 months ago
COVID-19 Research: Could Disulfiram- A Drug To Prevent Alcoholism, Aid In Inhibiting Cytokine Storms In COVID-19?
COVID-19 Research: Could Disulfiram- A Drug To Prevent Alcoholism, Aid In Inhibiting Cytokine Storms In COVID-19?
Source: Covid-19 Research  May 26, 2020  2 months ago
COVID-19 Research:  Medical researchers from Boston Children's Hospital have discovered that disulfiram, a US FDA-approved drug commonly used for treating alcoholism, blocks a key gatekeeper protein involved in inflammation, hence effectively inhibiting the inflammation process.


 
Typically, inflammation is the alarm system by which cells first respond to potential danger. But in excess, inflammation can be deadly.
 
Normally, the 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.
 
In animal model studies, mice treated with disulfiram did not develop fatal sepsis compared with untreated animals.
 
These research findings were published in a paper in Nature Immunology. https://www.nature.com/articles/s41590-020-0669-6
 
Dr Judy Lieberman,co-senior investigator of the study together with Dr Hao Wu, Ph.D., also in the PCMM (Program in Cellular and Molecular Medicine) and Professor of structural biology at Harvard Medical School told Thailand Medical News, "This research discovery is coincidentally very timely because most individuals think that the clinical deterioration of COVID-19 patients is mediated by a cytokine storm, or excessive release of inflammatory molecules.”
 
Dr Wu added, "Even though there has been a lot of interest, there have not been any bona fide gasdermin D inhibitors. We screened thousands of compounds and found that the one that worked best was disulfiram and it is already on the market, is inexpensive, has a 70-year history of drug safety, and could be repurposed pretty quickly."
 
It has been studied that when an invading virus or bacteria enter a cell, it triggers inflammation unleashing a cascade of events. One key event is called pyroptosis, or a fiery or inflammatory cell death. In pyroptosis, the cell's membrane literally explodes, releasing inflammatory molecules like interleukin-1, which causes fever.

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In a paper published in Nature in 2016, Lieberman and Wu discovered that gasdermin D forms membrane pores. When these pores open, inflammatory molecules spill out of the cell causing pyroptosis. https://www.nature.com/articles/nature18629?draft=collection
 
Also it is known that 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.
 
Dr Wu further added, "We knew that gasdermin D is the gatekeeper of the pathway leading to pyroptosis and spillage of inflammatory cytokines. If we could find a compound that would inhibit this particular step, that could be an attractive drug target to prevent pyroptosis when it was not needed."
 
Dr Jun Jacob Hu, Ph.D., screened more than 3,700 small molecules in the Wu lab looking for gasdermin D inhibitors. He found just 22 active compounds and disulfiram was at the top of the list.
 
Subsequently the research team studied mice sick with sepsis. They observed that disulfiram blocked pyroptosis and its explosive release of inflammatory molecules. Mice treated with disulfiram survived while those not receiving the drug died from sepsis within one day.
 
Dr Lieberman added, "There have been hundreds of clinical trials looking for drugs to stop sepsis and the overwhelming inflammatory response without success,".
 
To date, sepsis is the leading cause of death in children in the world and contributes to about a third of deaths in hospitalized adults.
 
Dr Lieberman commented, "We hope that with this new discovery, inhibiting gasdermin D that is in a critical location in the inflammatory pathway we could actually have a therapy that might work."
 
The research team is now looking to apply these findings to COVID-19.
 
Dr Wu explained, "As COVID-19 can produce an inflammatory syndrome that is very similar to sepsis, we wonder whether disulfiram can be used to treat severely ill COVID-19 patients. We know from a recent report that disulfiram also inhibits a coronavirus protease replication, one of the essential proteins of the SARS-CoV-2 coronavirus causing COVID-19."
 
Already plans are in place to study pyroptosis and coronavirus. The ultimate goal is to start a clinical trial with disulfiram in COVID-19 patients.
 
Dr Lieberman concluded, "The truth is that gasdermin D contributes to so much pathology in the body that we think an effective gasdermin D inhibitor like disulfiram could open up many therapeutic possibilities.”
 
The team is expected to start a clinical trial to treat COVId-19 patients as early as mid-June.
 
For more about COVID-19 Research, keep logging to Thailand Medical News
 
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