Rutgers researchers believe they are among the leaders in a race to find an oral COVID-19 treatment that complements or replaces Paxlovid, an antiviral drug that helps keep high-risk patients out of the hospital.
Your report, which will appear in Scienceshows that an alternative drug, a papain-like viral protease inhibitor, inhibits disease progression in animals, a necessary step before drug trials in humans.
“COVID-19 remains the third leading cause of death in the country, so there is already a huge need for additional treatment options,” said Jun Wang, lead author of the study and an associate professor who runs a research laboratory at the Rutgers Ernest Mario School of Science. Pharmacy. “That need will become more urgent when, inevitably, COVID-19 mutates in ways that prevent Paxlovid from working.”
The Rutgers team hoped to make a drug that would interfere with the viral papain-like protease (PLpro), a protein that plays important roles in all known strains of COVID-19.
Creating such a drug required detailed information about the structure of PLpro, which Wang’s team obtained from the Arnold Laboratory at the Center for Advanced Biotechnology and Medicine (CABM) at Rutgers.
Precise knowledge of the structure of PLpro allowed Wang’s team to design and synthesize 85 drug candidates that would bind to – and interfere with this vital protein.
“PLpro crystal structures showed an unexpected arrangement of how drug candidate molecules bind to their protein target, leading to innovative design ideas implemented by Professor Wang’s medicinal chemistry team,” said Eddy Arnold, professor at the CABM and the Rutgers Department. Chemistry and Chemical Biology.
Laboratory tests established that the most effective of those drug candidates, a compound called Jun12682, inhibited several strains of the SARS-CoV-2 virus, including strains that resist treatment with Paxlovid.
Subsequent testing in mice infected with SARS-CoV-2 by the Deng laboratory at Oklahoma State University showed that oral treatment with Jun12682 reduced lung viral loads and injury, while improving survival rates.
“Our treatment was as effective in mice as Paxlovid was in its initial animal tests,” Wang said, adding that the experimental drug appears to have at least one major advantage over the older drug.
“Paxlovid interferes with many prescription medications, and most people who face the highest risk of severe COVID-19 take other prescription medications, so it’s a real problem,” Wang said. “We tested our candidate Jun12682 against the leading drug-metabolizing enzymes and we saw no evidence that it would interfere with other medications.
Disclosure: Rutgers has filed patent applications for Jun12682, along with the other 84 drug candidates, and is seeking partners to help advance the drug candidate through new stages of testing and development.