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Research Outlines How Drug in Clinical Trial for Coronavirus Works

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A new study published in the Journal of Biological Chemistry outlines how an antiviral drug that is currently being tested in patients with the novel coronavirus (COVID-19), remdesivir, works.

Antiviral drugs are not yet approved for managing human coronaviruses, which is creating a wealth of challenges in the current efforts to contain the outbreak of COVID-19 which is caused by the SARS-CoV-2 virus. In order to survive and replicate, viruses must possess molecular machinery that can generate copies of their genetic material.

Coronaviruses are known to replicate their genetic material via an enzyme called RNA-dependent RNA polymerase. Remdesivir, developed by Gilead Sciences, is a nucleotide analogue that was originally created for the treatment of the Ebola virus.

Studies in cell culture and animal models have demonstrated that the drug has a wide range of antiviral effects against a number of viruses, including coronaviruses. In this study, scientists used polymerase enzymes from the coronavirus that causes Middle East Respiratory Syndrome (MERS) to further explore remdesivir's mechanism of action.

The work was led by Matthias Götte, a virologist and professor at the University of Alberta, Edmonton. He said: "It hasn't been easy to work with these viral polymerases". Due to this factor, previous work exploring the drugs function has been slow.

Götte and team discovered that the polymerase enzymes are able to incorporate remdesivir into their structure as it resembles an RNA building block, thereby "confusing" the enzyme. Upon this incorporation, the eznzyme can no longer add more RNA subunits, halting the replication of the virus' genetic material.

Why does this happen? The scientists suggest that the RNA containing remdesivir is a strange shape and therefore doesn't fit into the enzyme. To prove this hypothesis, they would need to obtain structural data on the enzyme and the synthesized RNA.

Remdesivir has not been approved as a drug anywhere in the world. According to Gilead, results from a clinical trial with COVID-19 patients in China are expected in April.

Gordon et al. (2020). The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. Journal of Biological Chemistry. DOI: 10.1074/jbc.AC120.013056.