Rensselaer Polytechnic Institute researchers will use a five-year, $3.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), to develop a low-dose, oral COVID antiviral drug that can be administered at home.

“Our role in the project is to develop novel inhibitors of the two key proteases of the SARS-CoV-2 virus, called CLpro and PLpro, which are essential to the virus life cycle,” says researcher Gaetano Montelione, the Constellation Endowed Chair of Structural Bioinformatics.

The team’s work will build upon Montelione’s previous research on COVID antiviral drug options. First, using bioinformatics, Montelione and his team found that a key protein from the hepatitis C virus closely resembles the coronavirus CLpro protease structure. Since several Food and Drug Administration (FDA)-approved drugs target the hepatitis C protease, the next step was to determine if any of those drugs would also bind and block proteases of SARS-CoV-2.

In research published in Cell Reports, the team found that, out of the 10 hepatitis C drugs tested, seven suppressed the SARS-CoV-2 virus. Three of those drugs were acting not only on the main protease, CLpro, but on the PLpro protease, as well. Next, they discovered that, when combined with the polymerase inhibitor remdesivir, these drugs multiplied remdesivir’s antiviral activity by as much as tenfold. Those that only inhibit CLpro did not amplify remdesivir’s effect.

“Inhibiting PLpro seems to be important,” says Christopher Cioffi, Thomas and Constance D’Ambra Endowed Chair of Organic Chemistry.

“This induces synergy with other antivirals such as remdesivir, which is currently being used to treat people with COVID-19. Now, we will work toward making new and orally bioavailable PLpro inhibitors based on Montelione’s biophysical analysis. We will look at the structure of the protein’s active site and design molecules that fit into it and bind with optimal affinity.”

CLpro will also be targeted.

“One of the big challenges is that the target will evolve to escape the drug,” Montelione says. “This is particularly problematic with rapidly mutating viruses like COVID-19. To overcome that, we try to hit multiple targets. By hitting both CLpro and PLpro simultaneously, there is less likelihood of antiviral resistance.”

It is hoped that the most promising COVID antiviral drug to come out of the AViDD centers will enter late-stage preclinical development. Industry partners will provide valuable resources to accelerate their movement through the product development pipeline. Drugs that are already FDA-approved for treating different diseases may be approved quicker for the treatment of COVID-19, as well.