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Use of Viral Entry Assays and Molecular Docking Analysis for the Identification of Antiviral Candidates against Coxsackievirus A16
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Amiloride is a competitive inhibitor of coxsackievirus B3 RNA polymerase

Elena V Gazina1, Eric D Smidansky, Jessica K Holien

  • 1Florey Neuroscience Institutes, The University of Melbourne, Victoria 3010, Australia. egazina@unimelb.edu.au

Journal of Virology
|July 29, 2011
PubMed

Insights

Amiloride and EIPA non-nucleoside inhibitors block coxsackievirus B3 RNA replication by inhibiting the viral RNA-dependent RNA polymerase 3D(pol) enzyme activity. This study reveals their competitive inhibition mechanism at the molecular level.

Area of Science:

  • Virology
  • Molecular Biology
  • Biochemistry

Background:

  • Amiloride and its derivative EIPA inhibit coxsackievirus B3 (CVB3) RNA replication in cell culture.
  • Specific mutations in the CVB3 RNA-dependent RNA polymerase (3Dpol) confer partial resistance to these compounds.

Purpose of the Study:

  • To investigate the enzymatic activity of CVB3 3Dpol in the presence of amiloride and EIPA.
  • To elucidate the molecular mechanism by which amiloride and EIPA inhibit CVB3 3Dpol.

Main Methods:

  • In vitro enzymatic assays of CVB3 3Dpol activity.
  • Analysis of VPg uridylylation and RNA elongation.
  • Molecular docking analysis to predict inhibitor binding sites.

Main Results:

  • Amiloride and EIPA inhibit both VPg uridylylation and RNA elongation by CVB3 3Dpol.
  • Amiloride acts as a competitive inhibitor, competing with nucleoside triphosphates (NTPs) and Mg(2+).
  • Docking analysis identified a binding site for amiloride and EIPA overlapping the nucleotide binding site of 3Dpol.

Conclusions:

  • This study provides the first molecular mechanism for non-nucleoside inhibition of a picornaviral RNA-dependent RNA polymerase.
  • Amiloride and EIPA's inhibition of CVB3 3Dpol offers potential therapeutic strategies against CVB3 infections.

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