Study sheds light on how a drug being tested in COVID-19 patients works

A team of academic and industry researchers is reporting new findings about how exactly an investigational antiviral drug stops coronaviruses. Their paper was published the same day that the National Institutes of Health announced that the drug in question, remdesivir, is being used in the nation's first clinical trial of an experimental treatment for COVID-19, the illness caused by the SARS-CoV-2 virus.

Previous research in cell cultures and animal models has shown that remdesivir can block replication of a variety of coronaviruses, but until now it hasn't been clear how it does so. The research team, which studied the drug's effects on the coronavirus that causes Middle East Respiratory Syndrome, reports that remdesivir blocks a particular enzyme that is required for viral replication. Their work was published in the Journal of Biological Chemistry.

All viruses have molecular machinery that copy their genetic material so that they can replicate. Coronaviruses replicate by copying their genetic material using an enzyme known as the RNA-dependent RNA polymerase. Until now, it has been difficult to get the polymerase complex that contains multiple proteins to work in a test tube.

"It hasn't been easy to work with these viral polymerases," Matthias Götte, a virologist and professor at the University of Alberta, Edmonton, who led the JBC study. That has slowed research into new drugs' function.

Using polymerase enzymes from the coronavirus that causes MERS, scientists in Götte's lab, including graduate student Calvin Gordon, found that the enzymes can incorporate remdesivir, which resembles an RNA building block, into new RNA strands. Shortly after adding remdesivir, the enzyme stops being able to add more RNA subunits. This puts a stop to genome replication.

The scientists hypothesize that this might happen because RNA containing remdesivir takes on a strange shape that doesn't fit into the enzyme. To find out for certain, they would need to collect structural data on the enzyme and newly synthesized RNA. Such data could also help researchers design future drugs to have even greater activity against the polymerase.

Götte's lab previously showed that remdesivir can stop the polymerase of other viruses with RNA genomes, such as Ebola. But, said Götte, the molecules that remdesivir and related drugs mimic are used for many different functions in the cell. This paper supports the viral RNA polymerase of coronaviruses as a target.

Calvin J Gordon, Egor P Tchesnokov, Joy Y Feng, Danielle P Porter, Matthias Gotte.
The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus.
JBC 2020. doi: 10.1074/jbc.AC120.013056.

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