Extinguish inflammation
Inflammation is an emergency system by which cells respond to potential danger, but excessive inflammation can lead to death.
Studies in mice conducted by Harvard Medical School and Boston Children's Hospital show that the FDA-approved drug disulfiram, commonly prescribed for the treatment of alcoholism, blocks a key gatekeeper protein involved in inflammation. The group screened thousands of compounds and found that the most effective drug is already on the market, is inexpensive, has a 70-year history of safe use and can be reconfigured fairly quickly.
Activation of the gatekeeper protein gasdermin D is the last stage in the process of inflammatory cell death (pyroptosis), accompanied by the release of inflammatory cytokines accumulated in them.
The scheme of disulfiram's participation in the cytokine storm.
Excessive inflammation is at the root of many serious conditions, including sepsis.
The researchers report that mice treated with disulfiram, unlike control animals, did not develop fatal sepsis. The results obtained give hope for victory over diseases accompanied by excessive inflammation, although it is not yet known whether the results obtained can be reproduced in humans.
This discovery is especially relevant today, because a number of scientists believe that the clinical deterioration of patients with COVID-19 is mediated by a cytokine storm – excessive release of inflammatory molecules.
Inflammatory cascade
When a virus or bacterium enters a cell, a cascade of inflammatory reactions is triggered. One of the key events is pyroptosis – inflammatory cell death. With pyroptosis, the cell membrane practically explodes, releasing inflammatory molecules (interleukin-1 and others) that cause fever.
In an article published in the journal Nature in 2016, the same group of authors found that gasdermine D forms membrane pores. When these pores open, inflammatory molecules exit the cell, causing pyroptosis.
Excessive inflammation contributes to the development of sepsis, inflammatory bowel diseases, gout, type II diabetes mellitus, cardiovascular diseases and Alzheimer's disease, and is a distinctive feature of rare genetic inflammatory diseases.
Calm pyroptosis
More than 3,700 small molecules were tested in search of gasdermine D inhibitors and only 22 active compounds were found. Disulfiram was at the top of this list.
Next, the group examined mice with sepsis and found that disulfiram blocks pyroptosis and the release of inflammatory molecules. Mice treated with disulfiram survived, and mice not taking the drug died of sepsis within one day.
COVID-19 studies are planned
Currently, a group of researchers is looking for ways to apply these results to the new coronavirus, since COVID-19 can cause an inflammatory syndrome very similar to sepsis, in order to understand whether disulfiram can be used to treat seriously ill patients. In addition, disulfiram has recently been shown to also inhibit coronavirus protease, one of the most important proteins of the virus that causes COVID-19.
Article J.J.Hu et al. The FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation is published in the journal Nature Immunology.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on materials from Harvard Medical School: Smothering the Fire.