A group of researchers in Russia have claimed that disulfiram (a drug used to treat alcoholism) and neratinib (a drug used for breast cancer treatment) may be effective against COVID-19.
The study was conducted by a chemist team from Zelinsky Institute of Organic Chemistry and HSE University in Russia. The findings of the study, published in the journal Mendeleev Communications, suggest that we should look for drugs that target conserved areas (those that do not change) in the SARS-CoV-2 virus.
Otherwise, a medicine effective against one strain of the virus may not be effective against another strain.
COVID-19 is a contagious disease that spreads through respiratory droplets and fomites. The disease has affected almost 19 million people already and has killed over 711,000.
Since the disease is so new and developing new drugs takes time, scientists and health practitioners around the world have been focusing on repurposing existing drugs to treat the condition. Whether it is the ebola drug remdesivir or the flu drug favipiravir, all the approved drugs for the disease had been developed previously.
The Mpro protein and molecular docking
Mpro is a protease (an enzyme) that the COVID-19 causing virus needs to make copies of itself inside the host cell. Since this enzyme is resistant to mutations, it is previously suggested to be an ideal target site for drugs. In fact, the HIV drugs lopinavir/ritonavir that have been suggested for COVID-19 treatment are a type of protease inhibitors that work on 3CLpro and PLpro (other proteases) of the SARS-CoV-2 virus.
The process of molecular docking is used to study how two compounds interact with each other. Usually, the ligand (the drug in this case) fits perfectly into the active site (Mpro here) to make a complex and leave an enzyme (in this case, SARS-CoV-2) useless. However, experts say that such a strong docking does not happen in SARS-CoV-2.
So, the researchers studied the structure of the Mpro protein to find new active sites that may be able to bind strongly with drugs and hence can be used to stop the enzyme from functioning.
Disulfiram and neratinib
Trying to find an effective drug for the disease, the researchers went through the list of FDA approved drugs and their metabolites and their ability to bind to Mpro active site.
It was found that sulfur-containing drugs can bind with a strong affinity to the active site of Mpro. However, only disulfiram makes stable complexes. This drug acts in two different ways. First, it acts as a covalent inhibitor of the Mpro enzyme as shown previously with MERS and SARS virus. Covalent inhibitors bind to the target enzyme and keep it from functioning. Second, it works against the reduction of glutathione (an antioxidant) in COVID-19 patients.
Glutathione therapy is suggested to be effective in the management of coronavirus disease. To deal with alcoholism, disulfiram acts on the enzyme acetaldehyde dehydrogenase and stops its functioning. This enzyme plays a role in the metabolism of ethanol in the liver and when it stops functioning, a compound called acetaldehyde grows in the person's body. This causes vomiting and pain and over time, the person starts to associate these symptoms with alcohol and starts to dislike it.
Neratinib, on the other hand, is a tyrosine kinase inhibitor and is used as an adjuvant (to improve the effectiveness of the original treatment) in the treatment of breast cancer. To stop breast cancer, this drug binds irreversibly to some receptors in cancer cells and keeps them from replicating.
In the case of SARS-CoV-2, neratinib also acts by covalent interaction, (like disulfiram) however, the type of interaction in both drugs is a bit different. As per a news release by HSE University, disulfiram can inhibit Mpro at a concentration of 100nm (nanomolar); the effect of neratinib is suggested to not be enough for clinical use.
For more information, read our article on COVID-19.
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