Rutgers Health researchers have developed an oral antiviral drug candidate for COVID-19 that could overcome major limitations of Paxlovid, currently the most prescribed oral treatment.
As with its predecessor, the new drug candidate, Jun13296, targets a different viral protein than Paxlovid does and works alone rather than in combination with another drug called ritonavir. But Jun13296 beats the same lab's first effort on several crucial metrics.
"This new compound is more potent than our first-generation candidate," said Jun Wang, senior author of the study published in Nature Communications and professor of medicinal chemistry at Rutgers' Ernest Mario School of Pharmacy. "In animal studies, our second-generation inhibitor still provides 90% protection at just one-third the dose of our initial compound and significantly outperforms it in reducing viral loads in the lungs."
It also addresses Paxlovid's major limitation: drug interaction-induced side effects.
"Most people who are at high risk of COVID-induced complications already take medications for diseases like high blood pressure or diabetes," Wang said. "A large percentage of them cannot take Paxlovid because of drug-drug interaction problems."
Wang's team designed the new compound to target a structure in the virus called its papain-like protease (PLpro) rather than the main protease targeted by Paxlovid.
In laboratory testing, Jun13296 remained effective against Paxlovid-resistant strains of the virus.
"We have data to confirm that our PLpro inhibitor retains potent inhibition against all the variants we have tested," Wang said.
The collaborator Xufang Deng's lab from the Oklahoma State University tested the compound in mice infected with SARS-CoV-2, the virus that causes COVID-19. Five-day survival rates were 90% for mice given Jun13296, 40% for those given the same low dose of the first-generation compound Jun12682 and 0% for untreated mice.
The drug also significantly reduced inflammation and viral levels in the lungs. At 75 milligrams per kilogram, Jun13296 provided strong inflammation protection, while the first-generation compound Jun12682 showed only moderate efficacy at this reduced dosage.
Most promising is that Jun13296 worked at comparable or lower doses than Paxlovid in similar animal models.
"If you look at the animal model which people have conducted with Paxlovid, they need to treat the mice with like 150 or even up to 300 milligrams per kilo to achieve similar efficacy," Wang said.
Efficacy at lower doses helps patients because it reduces the chance that a drug will have serious side effects, Wang said.
Unlike Paxlovid, Jun13296 shows no inhibition of major drug-metabolizing CYP450 enzymes in laboratory tests, suggesting it would not interfere with other medications and does not need to co-administer with ritonavir, thereby circumventing the drug interaction-induced side effects.
Significant contributions to this study were made by Eddy Arnold's Lab at Rutgers' Center for Advanced Biotechnology and Medicine (CABM), which solved the X-ray crystal structures of PLpro-critical for structure-based drug design.
Moving the drug toward human trials faces significant hurdles, primarily funding. Wang estimated the next phase will cost "tens of millions of dollars" beyond what academic labs can typically secure.
"Moving forward to investigational new drug application-enabling studies and human clinical trials, it can cost tens of millions of dollars," Wang said. "That's basically beyond what we can do in academia."
His team is looking to partner with pharmaceutical companies or non-profit organizations to advance the compound through the required pre-clinical studies and eventually to Food and Drug Administration applications.
The development comes as COVID-19 continues to evolve, including variants resistant to existing treatments. Wang said having multiple treatment options remains crucial for pandemic preparedness. Even if not immediately commercialized, completing early-stage clinical trials would mean reducing the time to get the treatment approved if SARS-CoV-2 evolves and causes another epidemic or pandemic.
The methodologies developed by the research team are broadly applicable to other infectious diseases beyond COVID-19. Wang's lab specializes in developing antivirals against multiple respiratory viruses, including influenza and enteroviruses.
Disclosure: Rutgers has submitted patent applications for Jun13296 and is looking for partners to help move the drug candidate forward through further stages of testing and development.
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