Research Alert
Newswise — Paxlovid (Nirmatrelvir/ritonavir) has been instrumental in treating COVID-19 infections, but negative interactions between ritonavir and other drugs have led some patients to be hospitalized with kidney failure. Molnupiravir, another antiviral under Emergency Use Authorization from the FDA, has not been nearly as effective at treating COVID-19.
In a new study, researchers at Yale School of Medicine have created a non-toxic potential alternative to Paxlovid by combining molnupiravir with a new, lab-developed antiviral compound. "Options for other COVD-19 drugs would be especially important for immunocompromised patients, particularly those who have received organ transplants," says Karen S. Anderson, PhD, professor of pharmacology and of molecular biophysics & biochemistry at Yale School of Medicine and an author of the study, "since they can experience toxicity due drug-drug interactions between their anti-rejection medication and Paxlovid."
Using computational analysis coupled with biochemical assays, researchers from the Jorgensen and Anderson labs found the seizure drug perampanel could loosely bind to the main protease of SARS-CoV-2, which is essential for viral replication. From there, they altered the drug's chemical structure to come up with compounds that might work in a preclinical setting.
The team of Priti Kumar, PhD, associate professor of internal medicine and an author of the study, found one of these compounds designed by the Jorgensen and Anderson labs - designated Mpro61 - had promise in a mouse model of SARS-CoV-2 infection. When Kumar's lab tested an oral formulation of Mpro61 along with molnupiravir, mice infected with COVID-19 showed no traces of the virus after 14 days of treatment. "All mice not only achieved a full recovery, they also experienced complete suppression of pulmonary inflammatory responses and showed no lung damage," Kumar says. "This is particularly significant as Molnupiravir by itself was unable to elicit this outcome."
Researchers say randomized clinical trials are needed to establish safety and efficacy in humans vs. COVID-19 and other coronaviruses. “We were so caught off guard with [the COVID- 19] pandemic in terms of having something that works,” Anderson says. “This work might put us a step forward in future pandemics.”
The study's lead authors were Christina Papini and Irfan Ullah. Co-authors included Shuo Zhang, Qihao Wu, Krasimir A. Spasov, Chunhi Zhang, Walther Mothes, Jason M. Crawford, Brett Lindenbach, Pradeep D. Uchil, and William L. Jorgensen.
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