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Journal of Virology, May 2008, p. 4720-4730, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.01338-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Thiazolobenzimidazole TBZE-029 Inhibits Enterovirus Replication by Targeting a Short Region Immediately Downstream from Motif C in the Nonstructural Protein 2C

Rega Institute for Medical Research, University of Leuven, Leuven, Belgium,¹ Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6500 HB Nijmegen, The Netherlands,² Laboratoire Architecture et Fonction des Macromolécules Biologiques UMR6098 CNRS and Université de la Méditérannée, Marseille, France,³ Dipartimento Farmaco-Chimico, Università di Messina, Messina, Italy,⁴ Institut für Pharmazie, Abteilung Pharmazeutische Chemie, Universität Innsbruck, Innsbruck, Austria,⁵ Institut für Virologie, The Calicilab, Medizinisch-Theoretisches Zentrum, Dresden, Germany⁶

Received 19 June 2007/ Accepted 3 March 2008

TBZE-029 {1-(2,6-difluorophenyl)-6-trifluoromethyl-1H,3H-thiazolo[3,4-a]benzimidazole} is a novel selective inhibitor of the replication of several enteroviruses. We show that TBZE-029 exerts its antiviral activity through inhibition of viral RNA replication, without affecting polyprotein processing. To identify the viral target of TBZE-029, drug-resistant coxsackievirus B3 (CVB3) was selected. Genotyping of resistant clones led to the identification of three amino acid mutations in nonstructural protein 2C, clustered at amino acid positions 224, 227, and 229, immediately downstream of NTPase/helicase motif C. The mutations were reintroduced, either alone or combined, into an infectious full-length CVB3 clone. In particular the mutations at positions 227 and 229 proved essential for the altered sensitivity of CVB3 to TBZE-029. Resistant virus exhibited cross-resistance to the earlier-reported antienterovirus agents targeting 2C, namely, guanidine hydrochloride, HBB [2-(alpha-hydroxybenzyl)-benzimidazole], and MRL-1237 {1-(4-fluorophenyl)-2-[(4-imino-1,4-dihydropyridin-1-yl)methyl]benzimidazole hydrochloride}. The ATPase activity of 2C, however, remained unaltered in the presence of TBZE-029.

Published ahead of print on 12 March 2008.