Journal of Virology vol:82 issue:10 pages:4720-4730
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 lead to the identification of 3 amino acid mutations in the non-structural protein 2C, clustered at amino acid positions 224, 227 and 229 immediately downstream of the NTPase/helicase motif C. The mutations were reintroduced, either alone or combined, in 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 anti-enterovirus agents targeting 2C, namely guanidine hydrochloride, HBB and MRL-1237. The ATPase activity of 2C, however, remained unaltered in the presence of TBZE-029.