Rutgers Health researchers have developed candidates for oral antiviral drugs for Covid-19 that may overcome the major limitations of Paxlovid and are currently prescribed for the most oral treatments.
Like its predecessor, the new drug candidate 13296 targets differently from the viral protein of paxlovid rather than working alone, rather than being used in combination with another drug called ritonavir. But Jun13296 beat the first effort of the same lab on several key metrics.
“This new compound is more effective than our first-generation candidates,” said Jun Wang, senior author of the study. Natural Communications Professor of Medicinal Chemistry at Ernest Mario School of Pharmacy at Rutgers. “In animal studies, our second-generation inhibitors still provide 90% protection, only one-third of the dose of our initial compound, and significantly outperformed it in reducing viral load in the lungs.”
It also addresses the main limitation of Paxlovid: side effects caused by drug interactions.
“Most of the people at high risk of co-certified complications have taken medication for diseases such as hypertension or diabetes,” Wang said. “A large proportion of them are unable to take paxlovid due to drug interaction issues.”
Wang’s team designed new compounds to target structures in a virus called papain protease (PLPRO), rather than the main protease targeted by paxlovid.
In laboratory tests, the anti-Paxlovid strain of the virus remained effective in June 13296.
“We have data to confirm that our PLPRO inhibitor retains effective inhibitory effects on all variants we tested,” Wang said.
The lab of Oklahoma State University collaborator Xufang Deng tested the compounds of mice infected with SARS-COV-2, the virus that causes COVID-19. The five-day survival rate for mice given Jun 13296 in 13296 was 90%, the survival rate for the first generation of the same dose of the first generation of the compound Jun12682 was 40%, and the survival rate for the untreated mice was 0%.
The drug also significantly lowers inflammation and viral levels in the lungs. In June 13296, 75 mg per kg, provided strong protection against inflammation, while the first generation compound Jun12682 showed only moderate efficacy at this reduced dose.
Most promising is that in similar animal models, the working dose of Jun 13296 is comparable or lower than that of Paxlovid.
“If you look at animal models people use Paxlovid, you need to achieve similar efficacy at 150 or even up to 300 mg per kilogram,” Wang said.
The lower dose efficacy helps patients because it reduces the chances of serious side effects from the drug, Wang said.
Unlike Paxlovid, in lab tests in June 13296, the primary drug metabolism CYP450 enzyme was not inhibited, suggesting that it does not interfere with other drugs and does not require co-management with Ritonavir, thus avoiding the side effects induced by drug interactions.
The laboratory of Eddy Arnold at Rutgers’ Center for Advanced Biotechnology and Medicine (CABM) has made a significant contribution to the study, which addressed the X-ray crystal structure of PLPRO, which is crucial for structure-based drug design.
Turning drugs to human trials is a huge obstacle, mainly funding. Wang estimates that the next phase will cost “ten millions of dollars”, not something academic labs can usually ensure.
“Moving forward to research-based new drug applications and human clinical trials can cost tens of millions of dollars,” Wang said. “This is basically beyond what we can do in academia.”
His team is seeking to work with pharmaceutical companies or nonprofits to advance the compound through the required preclinical research, ultimately with the Food and Drug Administration’s application.
With the ongoing development of Covid-19, the development has evolved, including variants that are resistant to existing therapies. Having multiple treatment options remains crucial for pandemic preparation, Wang said. Even if not commercialized immediately, completing early clinical trials means reducing the time to approved treatment if SARS-COV-2 evolves and causes another epidemic or pandemic.
The method developed by the research team is widely applicable to other infectious diseases other than Covid-19. Wang’s lab specializes in developing antiviral drugs for a variety of respiratory viruses, including influenza and enteroviruses.
If our report has been informed or inspired, please consider donating. No matter how big or small, every contribution allows us to continue to provide accurate, engaging and trustworthy scientific and medical news. Independent news takes time, energy and resources – your support ensures that we can continue to reveal the stories that matter most to you.
Join us to make knowledge accessible and impactful. Thank you for standing with us!
