Journal News

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

Laurel Oldach
February 27, 2020

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.

Adapted from Gordon et al., JBC 2019
A figure from the paper shows the structures of ATP and the active metabolite of remdesivir, which has some important structural differences. 

All viruses have molecular machinery that copies their genetic material so 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, which contains multiple proteins, to work in a test tube.

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

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

Remdesivir, which is manufactured by the American company Gilead Sciences, 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.

The JBC study was funded by the Canadian Institutes of Health Research and the Alberta Ministry of Economic Development, Trade and Tourism. Two of its authors are Gilead scientists, because Gilead provided a form of the investigational drug free of charge. Götte has previously received funding from Gilead Sciences to support a study of remdesivir’s effect on enzymes from ebolavirus.

Laurel Oldach

Laurel Oldach is a science writer for the ASBMB.

Join the ASBMB Today mailing list

Sign up to get updates on articles, interviews and events.

Latest in Science

Science highlights or most popular articles

From the journals: JBC
Journal News

From the journals: JBC

July 14, 2020

A metal ion that transforms tau. A new target to take out cancer cells. One substitution that abolishes enzyme allostery. Read about recent papers on these topics and more in the Journal of Biological Chemistry.

COVID-19 retractions show that the science is working as it should
Life in the Lab

COVID-19 retractions show that the science is working as it should

July 12, 2020

Severe scrutiny of two major papers, including one about the effectiveness of hydroxychloroquine, is part of science's normal process of self-correction, explains Mark R. O’Brian.

In the future, lab mice will live in computer chips, not cages
Life in the Lab

In the future, lab mice will live in computer chips, not cages

July 11, 2020

As COVID-19 shuttered laboratories across the U.S., many researchers were forced to euthanize the animals they study. Lindsay Gray, a rodent surgeon in an animal research lab that faced this dilemma, argues here there is a safer, more effective way.

Proteomics reveals hallmarks of aging in brain stem cells
Journal News

Proteomics reveals hallmarks of aging in brain stem cells

July 09, 2020

Early in adulthood, the brain regenerates lost myelin effectively, but remyelination falters with age. Researchers seek to understand why — and what the change may mean for people with multiple sclerosis.

Ocean virus hijacks carbon-storing bacteria
Journal News

Ocean virus hijacks carbon-storing bacteria

July 07, 2020

A Journal of Biological Chemistry paper reports that these minuscule interactions could have ripple effects on global carbon dioxide levels.

CRISPR nanoparticles are the next big hope in Alzheimer’s disease treatments
News

CRISPR nanoparticles are the next big hope in Alzheimer’s disease treatments

July 04, 2020

Nearly 6 million Americans live with Alzheimer’s disease without solid treatment options.