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Journal of Virology, January 2009, p. 58-64, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01543-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antiviral Activity of the Zinc Ionophores Pyrithione and Hinokitiol against Picornavirus Infections {triangledown}

B. M. Krenn,1 E. Gaudernak,1 B. Holzer,1 K. Lanke,2 F. J. M. Van Kuppeveld,2 and J. Seipelt1*

Max F. Perutz Laboratories, Medical University of Vienna, Dr. Bohr-Gasse 9/3, 1030 Vienna, Austria,1 Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands2

Received 22 July 2008/ Accepted 6 October 2008

We have discovered two metal ion binding compounds, pyrithione (PT) and hinokitiol (HK), that efficiently inhibit human rhinovirus, coxsackievirus, and mengovirus multiplication. Early stages of virus infection are unaffected by these compounds. However, the cleavage of the cellular eukaryotic translation initiation factor eIF4GI by the rhinoviral 2A protease was abolished in the presence of PT and HK. We further show that these compounds inhibit picornavirus replication by interfering with proper processing of the viral polyprotein. In addition, we provide evidence that these structurally unrelated compounds lead to a rapid import of extracellular zinc ions into cells. Imported Zn2+ was found to be localized in punctate structures, as well as in mitochondria. The observed elevated level of zinc ions was reversible when the compounds were removed. As the antiviral activity of these compounds requires the continuous presence of the zinc ionophore PT, HK, or pyrrolidine-dithiocarbamate, the requirement for zinc ions for the antiviral activity is further substantiated. Therefore, an increase in intracellular zinc levels provides the basis for a new antipicornavirus mechanism.

* Corresponding author. Mailing address: Max F. Perutz Laboratories, Medical University of Vienna, Dr. Bohr-Gasse 9/3, 1030 Vienna, Austria. Phone: 43 1 427761610. Fax: 43 1 42779616. E-mail: joachim.seipelt{at}meduniwien.ac.at

{triangledown} Published ahead of print on 15 October 2008.

Journal of Virology, January 2009, p. 58-64, Vol. 83, No. 1
0022-538X/09/$08.00+0     doi:10.1128/JVI.01543-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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