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The nucleoside analog 4'-fluorouridine suppresses the replication of multiple enteroviruses by targeting 3D

Yongkang Chen1, Xiaohong Li2, Fengyang Han3

  • 1Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.

Antimicrobial Agents and Chemotherapy
|April 30, 2024
PubMed

Insights

4'-fluorouridine (4'-FlU) shows broad-spectrum antiviral activity against enteroviruses, inhibiting viral replication by targeting the 3D polymerase. This nucleoside analog offers a promising therapeutic candidate for enterovirus infections lacking current treatments.

Area of Science:

  • Virology
  • Infectious Diseases
  • Drug Discovery

Background:

  • Human enteroviruses are significant global pathogens responsible for hand-foot-and-mouth disease and severe complications like meningitis and myocarditis.
  • Current therapeutic options for enterovirus infections are limited, highlighting the urgent need for effective antiviral agents.

Purpose of the Study:

  • To identify and characterize novel antiviral compounds against a range of human enteroviruses.
  • To investigate the mechanism of action of promising antiviral candidates.

Main Methods:

  • Screening of nucleoside analogs for antiviral activity against multiple enterovirus strains.
  • Determination of EC50 values for effective antiviral concentrations.
  • Investigating the interaction of the compound with the enterovirus 3D RNA-dependent RNA polymerase (3Dpol).

Main Results:

  • 4 '-fluorouridine (4 '-FlU) demonstrated broad-spectrum antiviral activity against diverse enteroviruses, including coxsackievirus strains and enterovirus A71, with EC50 values in the low micromolar range.
  • 4 '-FlU was found to directly inhibit the RNA-dependent RNA polymerase (3Dpol) activity of enteroviruses.
  • This inhibition of 3Dpol activity led to suppressed viral RNA synthesis and replication.

Conclusions:

  • 4 '-fluorouridine is a potent inhibitor of enterovirus replication through direct targeting of the viral polymerase.
  • 4 '-FlU represents a promising direct-acting antiviral agent for the development of novel therapies against enterovirus infections.
Keywords:
3D polymerase4′-fluorouridineRdRpantiviral agentscoxsackievirusenterovirus

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