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4'-Fluorouridine mitigates lethal infection with pandemic human and highly pathogenic avian influenza viruses. | LitMetric

AI Article Synopsis

  • Influenza outbreaks cause significant health issues and economic challenges, highlighting the need for new antiviral treatments to combat both seasonal infections and potential pandemics from avian influenza viruses.
  • The study investigates the effectiveness of the nucleoside analog 4'-Fluorouridine (4'-FlU) against various influenza A and B viruses, demonstrating its strong inhibitory action and unique mechanism of targeting the influenza virus polymerase.
  • Administering 4'-FlU orally in animal models showed promising results, with rapid cessation of virus spread in ferrets and complete survival in mice after lethal infections, indicating its potential as a candidate for treating seasonal and pandemic influenza.

Article Abstract

Influenza outbreaks are associated with substantial morbidity, mortality and economic burden. Next generation antivirals are needed to treat seasonal infections and prepare against zoonotic spillover of avian influenza viruses with pandemic potential. Having previously identified oral efficacy of the nucleoside analog 4'-Fluorouridine (4'-FlU, EIDD-2749) against SARS-CoV-2 and respiratory syncytial virus (RSV), we explored activity of the compound against seasonal and highly pathogenic influenza (HPAI) viruses in cell culture, human airway epithelium (HAE) models, and/or two animal models, ferrets and mice, that assess IAV transmission and lethal viral pneumonia, respectively. 4'-FlU inhibited a panel of relevant influenza A and B viruses with nanomolar to sub-micromolar potency in HAE cells. In vitro polymerase assays revealed immediate chain termination of IAV polymerase after 4'-FlU incorporation, in contrast to delayed chain termination of SARS-CoV-2 and RSV polymerase. Once-daily oral treatment of ferrets with 2 mg/kg 4'-FlU initiated 12 hours after infection rapidly stopped virus shedding and prevented transmission to untreated sentinels. Treatment of mice infected with a lethal inoculum of pandemic A/CA/07/2009 (H1N1)pdm09 (pdmCa09) with 4'-FlU alleviated pneumonia. Three doses mediated complete survival when treatment was initiated up to 60 hours after infection, indicating a broad time window for effective intervention. Therapeutic oral 4'-FlU ensured survival of animals infected with HPAI A/VN/12/2003 (H5N1) and of immunocompromised mice infected with pdmCa09. Recoverees were protected against homologous reinfection. This study defines the mechanistic foundation for high sensitivity of influenza viruses to 4'-FlU and supports 4'-FlU as developmental candidate for the treatment of seasonal and pandemic influenza.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10138230PMC
http://dx.doi.org/10.1371/journal.ppat.1011342DOI Listing

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