Mechanism of action revealed for remdesivir, potential coronavirus drug

A team of academic and industry researchers has reported new findings on how exactly an investigational antiviral drug stops coronaviruses. The paper was published the same day that the US National Institutes of Health (NIH) announced that the drug in question, remdesivir, is being used in the country’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 has not been clear how it does so. The researchers, from the University of Alberta, US, and Gilead, studied the drug’s effects on the coronavirus that causes Middle East Respiratory Syndrome (MERS). They found that remdesivir blocks a particular enzyme that is required for viral replication. 

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 who led the study. He explained that this has slowed research into new drugs’ function. 

Using polymerase enzymes from the coronavirus that causes MERS, scientists in Götte’s lab 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 halts genome replication.

The scientists hypothesise that this might happen because RNA containing remdesivir takes on a strange shape that does not fit into the enzyme. To find out for certain, they would need to collect structural data on the enzyme and newly synthesised RNA. Such data could also help researchers design future drugs to have even greater activity against the polymerase. They suggest the viral RNA polymerase of coronaviruses as a target.

The study was published in the Journal of Biological Chemistry.