COVID-19 – A Detailed Research on the Efficacy of 4’-FlU as a Next-Generation Antiviral for Influenza

Despite the availability of FDA-approved antiviral drugs, the treatment of influenza remains challenging due to narrow therapeutic time windows, poor patient compliance, and impaired immune responses in older adults

. This research aims to explore the efficacy of 4’-FlU, a broad-spectrum antiviral ribonucleoside analog, in the treatment of seasonal, pandemic, and highly pathogenic avian influenza (HPAI) strains.

Methods: The study conducted antiviral potency assessments in cell culture, human airway epithelium cells, and in vivo infection models using ferrets and mice. 4’-FlU, previously shown to exhibit activity against SARS-CoV-2 and other respiratory viruses, demonstrated efficacy by incorporating into nascent RNA strands and inducing polymerase chain termination.

The molecule 4’-FlU, also known as 4’-fluorouridine, is a broad-spectrum antiviral ribonucleoside analog. It possesses antiviral properties against influenza viruses, respiratory syncytial virus (RSV), SARS-CoV-2, and other RNA viruses. Understanding how 4’-FlU works involves examining its mechanism of action and its impact on viral replication.

Mechanism of Action:
4’-FlU exerts its antiviral effects by interfering with viral RNA synthesis. It is metabolized within infected cells to its active form, 4’-FlU-triphosphate (4’-FlU-TP). The active triphosphate form competes with the natural nucleoside triphosphates (NTPs) during viral RNA replication. Once incorporated into the nascent RNA strand by the viral RNA-dependent RNA polymerase (RdRP), 4’-FlU-TP acts as a chain terminator, preventing further elongation of the RNA molecule. This disruption of viral RNA synthesis inhibits the replication and propagation of the virus.

Specificity and Variations in Mode of Action:
The mode of action of 4’-FlU may vary depending on the specific virus and its polymerase complex. In the case of influenza viruses, the RdRP stalls immediately upon incorporation of 4’-FlU-TP, leading to immediate termination of the RNA chain. However, in other viruses like RSV and SARS-CoV-2, the termination is delayed and depends on the sequence context. Multiple incorporations of 4’-FlU moieties in close repetition may be required for termination in these viruses. The precise mechanisms underlying these variations in mode of action are still under investigation.

Impact on Viral Replication:
By inducing chain termination and interfering with polymerase processivity, 4’-FlU disrupts viral replication. The incorporation of 4’-FlU alters the secondary structure of the nascent RNA strand, hindering the proper functioning of the viral polymerase and preventing the synthesis of full-length RNA molecules. As a result, viral replication is inhibited, reducing the viral load within infected cells.

Results: Resistance to the antiviral drug baloxavir marboxil emerged rapidly in clinical trials, leading to viral replication rebound in treated patients. However, whole genome sequencing of 4’-FlU-experienced virus populations did not show significant genetic divergence. The study found that 4’-FlU was highly potent against influenza viruses, respiratory syncytial virus (RSV), and SARS-CoV-2, with lower sensitivity observed in RSV and SARS-CoV-2.

In animal models, 4’-FlU demonstrated therapeutic efficacy even when administered up to 60 hours after infection, widening the therapeutic time window compared to other antivirals.

Discussion: The efficacy of 4’-FlU in treating influenza is attributed to its distinct mechanism of action and efficient intracellular metabolism. The drug significantly improved survival rates and reduced lung virus burden in treated animals. Additionally, 4’-FlU demonstrated potential for mitigating immunopathogenesis without impairing the development of a robust humoral and cell-mediated immune response. In a ferret transmission model, 4’-FlU reduced viral shedding and suppressed the spread of the virus to untreated sentinels.

Conclusion: The research findings suggest that 4’-FlU holds promise as a next-generation antiviral for influenza. Its broad-spectrum activity, ability to widen the therapeutic time window, and effectiveness in reducing viral replication and transmission make it a potential candidate for pandemic preparedness and the management of seasonal and highly pathogenic influenza strains. Further studies are needed to assess the genetic barrier against viral escape and to determine its efficacy in human clinical trials.

REFERENCE LINK : https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011342