Simian varicella virus (SVV) and human varicella-zoster virus (VZV) are closely related viruses that share many structural and functional properties. 5-Substituted 2'-deoxyuridine derivatives (e.g., BVDU, BVaraU) and acyclic guanine nucleoside derivatives (i.e., ACV and GCV) show comparable antiviral efficacy against VZV and SVV in cell culture. In contrast, the novel bicyclic nucleoside analogues (BCNAs) are exquisitely inhibitory to VZV (EC50 in the lower nanomolar range) but completely inactive against SVV. The VZV-cncoded thymidine kinase (TK) appeared to be essential for BCNA activation (phosphorylation) and anti-VZV activity. Also SVV TK is able to recognize the BCNAs as substrate, although with a different structure affinity relationship. Thus, viral TK-catalyzed phosphorylation is necessary but not sufficient for the BCNAs to display antiviral activity. Our data suggest that the eventual target of the BCNAs against VZV is either absent in SVV or, alternatively, is insensitive for the (phosphorylated) BCNAs. (C) 2004 Elsevier Inc. All rights reserved.