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Journal of Virology, February 2008, p. 1465-1473, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01374-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Amiloride Derivatives Inhibit Coxsackievirus B3 RNA Replication{triangledown}

David N. Harrison,1,2,{dagger} Elena V. Gazina,1,{dagger} Damian F. Purcell,2 David A. Anderson,3,4 and Steven Petrou1*

Howard Florey Institute, University of Melbourne, Parkville, Victoria 3010,1 Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria 3010,2 Macfarlane Burnet Institute, 85 Commercial Road, Melbourne, Victoria 3004,3 Select Vaccines Ltd., 15/545 St. Kilda Road, Melbourne, Victoria 3000, Australia4

Received 25 June 2007/ Accepted 12 November 2007

Amiloride derivatives are known blockers of the cellular Na+/H+ exchanger and the epithelial Na+ channel. More recent studies demonstrate that they also inhibit ion channels formed by a number of viral proteins. We previously reported that 5-(N-ethyl-N-isopropyl)amiloride (EIPA) modestly inhibits intracellular replication and, to a larger extent, release of human rhinovirus 2 (HRV2) (E. V. Gazina, D. N. Harrison, M. Jefferies, H. Tan, D. Williams, D. A. Anderson and S. Petrou, Antiviral Res. 67:98-106, 2005). Here, we demonstrate that amiloride and EIPA strongly inhibit coxsackievirus B3 (CVB3) RNA replication and do not inhibit CVB3 release, in contrast to our previous findings on HRV2. Passaging of plasmid-derived CVB3 in the presence of amiloride generated mutant viruses with amino acid substitutions in position 299 or 372 of the CVB3 polymerase. Introduction of either of these mutations into the CVB3 plasmid produced resistance to amiloride and EIPA, suggesting that they act as inhibitors of CVB3 polymerase, a novel mechanism of antiviral activity for these compounds.

* Corresponding author. Mailing address: Howard Florey Institute, The University of Melbourne, Victoria 3010, Australia. Phone: 61 3 8344 1957. Fax: 61 3 9347 0446. E-mail: spetrou{at}unimelb.edu.au

{triangledown} Published ahead of print on 21 November 2007.

{dagger} D.N.H. and E.V.G. contributed equally to this study.

Journal of Virology, February 2008, p. 1465-1473, Vol. 82, No. 3
0022-538X/08/$08.00+0     doi:10.1128/JVI.01374-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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