4’-fluorouridine and its derivatives as potential COVID-19 oral drugs: a review

Abstract

Background: Although vaccination is underway, antiviral drugs against coronavirus disease 2019 (COVID-19) are lacking. Remdesivir, a nucleoside analog that works by inhibiting the viral RNA-dependent RNA polymerase (RdRp), is the only fully approved antiviral for the treatment of COVID-19. However, it is limited to intravenous use and is usually recommended only for hospitalized patients with severe COVID-19; therefore, oral drugs that can be prescribed even to non-hospitalized patients are required. According to a recent study, 4′-fluoruridine, a nucleoside analog similar to remdesivir, is a promising candidate for COVID-19 oral therapy due to its ability to stall viral RdRp. Methods: We examined the antiviral activity of 4′-fluorouridine and compared it to other drugs currently in development. The current literature on 4′-fluorouridine's antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been compiled and discussed in this review. Results: The 4'-fluorouridine has antiviral activity against the respiratory syncytial virus, hepatitis C virus, lymphocytic choriomeningitis virus, and other RNA viruses, including SARS-CoV-2. In vitro studies have shown that SARS-CoV-2 is susceptible to 4'-fluorouridine, with the half-maximal effective concentration (EC50) of 0.2 to 0.6 M, and that the 4′-fluorouridine derivative, 4′-fluorouridine-5′-triphosphate, inhibited RdRp via a mechanism distinct from that of the already approved COVID-19 oral drug, molnupiravir. In addition, an in vivo study revealed that SARS-CoV-2 is highly susceptible to 4'-fluorouridine and was effective with a single daily dose versus molnupiravir administered twice daily. Conclusions: Concerns about the genetic effects of molnupiravir may be resolved by the use of 4′-fluorouridine and its derivative, which, unlike molnupiravir, do not alter genetics, but inhibit RdRp instead. Although they are currently considered as strong candidates, further studies are required to determine the antiviral activity of 4′-fluorouridine and its derivative against SARS-CoV-2 and their genetic effects on humans.