New mechanism of action against SARS-CoV-2 by antiviral drug remdesivir

Scientists at the University of Alberta can see a novel, second system of action by the antiviral medication remdesivir against SARS-CoV-2, based on findings published today within the Journal of Biological Chemistry.

The research team previously demonstrated how remdesivir inhibits the COVID-19 virus’s polymerase or replication machinery in a test tube.

Matthias Götte, chair of health care immunology and microbiology inside the Faculty of Treatments & Dentistry, likened the polymerase to the motor of herpes. He said the initial mechanism the group identified is much like putting diesel energy into an motor that really needs regular gasoline.

“Imaginable that in the event that you give it increasingly more diesel, you shall go slower and slower and slower,” he said.

The identified mechanism is a lot more like a roadblock newly, “when you want to go from the to B with the incorrect fuel and terrible road conditions, you either reach B or you arrive extremely late never,” Götte said.

“Remdesivir stops or heavily delays replication of the herpes virus, which often reduces spread and propagation.”

Götte said it’s not common for antiviral drugs to own multiple mechanism of action. The very first mechanism his team uncovered affects what’s called the “primer strand” of RNA or the very first copy herpes makes of the viral genome because it infects a cell. The 2nd mechanism affects the “template strand” that is repeated repeatedly since the virus spreads.

Clinical trials of remdesivir in COVID-19 patients are underway round the global world, including one run by the U.S. National Institutes of Health which reported preliminary results showing the typical recovery time for treated patients was shortened to 11 days in contrast to 15 days for the placebo group.

Götte said you will need to discover how remdesivir works as it could be the only direct-acting antiviral currently approved for conditional and/or emergency use as a COVID-19 treatment in many countries, including Canada and the U.S.

“Meaning remdesivir is just a benchmark that we have to understand in great detail so that you can build on it also to improve therapies later on,” Götte said.

Next steps for human trials and laboratory studies

Götte said that while remdesivir looks promising in laboratory tests and in cell cultures, he’s anxious to see more results from human clinical trials, particularly how remdesivir affects the “viral load” or quantity of virus in patients.

“Is there an improvement regarding whether somebody features a low viral load right from the start or even a high viral load? We do not know that yet,” he stated.

He said laboratory results may differ from human trials because there might be reservoirs of the virus in the human body that the drug does not reach. SARS-CoV-2 may develop resistance to the drug also, although he thinks this will be difficult based on what is known about how remdesivir interacts with other coronaviruses.

“We truly need these data to simply help us to higher understand which patients will take advantage of remdesivir,” he said.

Götte’s lab will continue wanting to understand more about how precisely remdesivir as well as other polymerase inhibitors work against SARS-CoV-2 to help drug discovery and development.

The extensive research was supported by the Canadian Institutes of Health Research, Gilead Sciences and the Alberta Ministry of Jobs, Innovation and economy.