A group of researchers at the University of Alberta, Canada claim that prodrug GC376, which is used to treat a potentially fatal feline coronavirus disease, is effective against the COVID-19 causing virus, SARS-CoV-2.
Prodrugs are compounds that have to be metabolised inside the body before they become active. GC376 gets converted to GC373.
The study, published in the peer-reviewed journal Nature Communications, suggests that the drug targets an enzyme called Mpro in the COVID-19 causing virus and is a strong drug candidate for the treatment of coronavirus disease since it is already shown to be effective in animals.
The research team is set to launch phase 1 clinical trials of the drug soon.
Feline coronavirus (FCoV)
Feline coronavirus FCoV, is a common infection that affects about 25 to 40 percent of domestic cats in the world. The virus enters a cat’s body through the oral route (licking, for example) and multiplies in the intestines. The cat will expel the virus in its feces where the virus may survive for up to a few weeks. Disinfectants readily destroy the feline coronavirus.
Most cats that get this infection are asymptomatic. However, they may develop a mild form of diarrhea or it could lead to a life-threatening condition called feline infectious peritonitis (FIP). The latter only develops when the FCoV virus develops a mutant strain inside the intestinal tract of the cat that can infect macrophages (a type of immune system cell) and spread throughout the body.
FCoV is an alpha-coronavirus while SARS-CoV-2 is a beta-coronavirus. The former does not cause infection in humans though there have been some cases where scientists found SARS-CoV-2 neutralising antibodies in cats.
Protease inhibitors and the latest drug
Proteases are enzymes that are crucial to the functioning of cells. Proteases inhibitors are one of the most common classes of drugs that are considered for the treatment of diseases when they show low toxicity. Proteases like Tipranavir have been used to treat HIV. Other HIV drugs like lopinavir and ritonavir are also proteases.
Mpro is a protease present in SARS-CoV-2 virus that helps the virus replicate and make copies of itself. This protease has previously been suggested to be resistant to mutations and hence a lot of experts have been looking for inhibitors that can stop the Mpro protease from functioning.
Various other Mpro inhibitors, including ebselen, an investigational drug for hearing loss and disulfiram, a drug used to treat alcoholism, have previously shown to be effective against the COVID-19-causing virus.
GC376 has been proposed to have broad specificity against the Mpro of the novel coronavirus previously. To study the effect of this drug against the SARS-CoV-2 virus, the researchers exposed the virus to the drug in cell cultures.
It was found that GC376 when incubated with SARS-CoV-2 converts to GC373, which binds to the active site of Mpro protease, inhibiting the function of the protease. The active site of an enzyme is a pocket in the enzyme wherein the substrate (the compound an enzyme acts on) binds to it.
“We determined the three-dimensional shape of the protease with the drug in the active site pocket, showing the mechanism of inhibition. This will allow us to develop even more effective drugs,” said Joanne Lemieux, corresponding author of the study and a professor of biochemistry at the University of Alberta, Canada in a news release by the university.
She also added that the team will keep on looking for modified versions of this drug which would fit even better in the active site of Mpro and would thus be more effective.
For more information on coronavirus types, read our article on Coronavirus infection.
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