New research shows how remdesivir works to inhibit coronavirus.
Remdesivir is the only treatment of its kind currently approved in the US for the coronavirus.
The findings could lead to more effective antiviral treatments.
Remdesivir targets a part of the coronavirus that allows it to make copies of itself and spread through the body. For the first time, scientists identified a critical mechanism that the drug uses and unearthed information that drug companies can use to develop new and improved antivirals to take advantage of the same trick.
The finding could also lead to more potent drugs, meaning a patient could take less of a dose, see fewer side effects, and experience faster relief, says Kenneth Johnson, professor of molecular biosciences at the University of Texas at Austin and coauthor of the paper in Molecular Cell.
“Right now, it’s a five-day regimen of taking quite a bit of remdesivir,” says Johnson. “That’s inconvenient and comes with side effects. What if you could take just one pill and that was all you needed to do? That would make a huge difference in terms of the here and now.”
Coauthor David Taylor, an assistant professor of molecular biosciences, likens the trick the team identified to a paper jam in the virus’s photocopier.
“This is not the last unique coronavirus that’s going to come after us,” Johnson says. “Having better antivirals could buy us time to develop vaccines against potential future outbreaks.”
Remdesivir shuts down this photocopier—called an RNA polymerase—by preventing copying of the virus’s genetic code and its ability to churn out duplicates and spread through the body. The team detected where the drug manages to gum up the gears, grinding the machine to a halt.
“We were able to identify the point where that paper jam happens,” says Taylor. “We know now exactly what’s creating this block. So, if we want to make the blockage even worse, we could do so.”
The search for more potent antivirals could soon become more urgent as new strains of SARS-CoV-2, the virus that causes COVID-19, regularly emerge.
“We might need other drugs that are like remdesivir, but different enough that they can then go after the mutated forms,” Johnson says. “It’s like having a backup system, like having an emergency parachute in case the main chute doesn’t work.”
The team recreated in a lab dish the process that plays out in a patient who is infected with SARS-CoV-2 and then receives remdesivir. In a scientific first, the scientists developed a method for producing fully functional RNA polymerases to copy the viral genetic material. Next, they added a form of remdesivir.
As the drug did its work, the researchers paused the process just after the reaction with remdesivir was completed (15-20 seconds) and took a 3D snapshot of the molecules in exquisite detail using a cryo-electron microscope in UT Austin’s Sauer Structural Biology Laboratory. The image allowed them to reconstruct exactly how remdesivir gums up the copying process.
SARS-CoV-2 is the third coronavirus to make the leap from animals to humans in less than 20 years, Johnson says. So even if this pandemic is brought under control soon, it still makes sense to continue developing weapons against coronaviruses.
“This is not the last unique coronavirus that’s going to come after us,” Johnson says. “Having better antivirals could buy us time to develop vaccines against potential future outbreaks.”
The Welch Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health, the National Institute of General Medical Sciences of the NIH, Army Research Office, and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation funded the work.
Source: University of Texas at Austin
