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Drug Discovery


4′-Fluorouridine fights respiratory viruses, including SARS-CoV-2, in animals

If effective in humans, the oral antiviral could be dosed less frequently than antivirals currently seeking regulatory approval

by Bethany Halford
December 9, 2021

The ribonucleoside analog 4'-fluorouridine treats infections of SARS-CoV-2, the virus that causes COVID-19, in ferrets and treats respiratory syncytial virus (RSV) infections in mice. The compound can be taken orally, and if it is effective in people, it could add to the growing antiviral arsenal.

Structure of 4′-fluorouridine.

4'-Fluorouridine targets the RNA-dependent RNA polymerase in RNA viruses—the same enzyme targeted by Merck’s oral antiviral molnupiravir, which was recently granted emergency use authorization by the US Food and Drug administration. But 4'-fluorouridine’s mechanism is distinct from molnupiravir’s, says Georgia State University’s Richard K. Plemper, who led the research on the new antiviral. While molnupiravir introduces errors in the viral replication process, which produces mutants of the virus that aren’t viable, 4'-fluorouridine causes the polymerase to stall so the virus’s genome doesn’t get copied (Science 2021, DOI: 10.1126/science.abj5508).

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Molnupiravir must be taken twice daily, but in animal studies, Plemper’s team found that 4'-fluorouridine was effective with a single daily dose. Less frequent dosing could boost compliance, the researchers say.

In tests with ferrets, 4'-fluorouridine was effective at fighting SARS-CoV-2 12 hours after initial infection with the virus. The disease progresses faster in ferrets than it does in humans, Plemper says, so 12 hours in ferrets should correspond to several days post-infection in people. In tests with mice, 4'-fluorouridine treated RSV infections up to 24 hours after infection.


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