On the basis of its favourable antiviral and pharmacokinetic properties, FV-100 is now being pursued as the clinical BCNA candidate for the treatment of VZV shingles.

Varicella-zoster virus (VZV) is responsible for primary infections as well as reactivations after latency inVaricella-zoster virus (VZV) is an alphaherpesvirus that is known to be responsible for varicella in young children and for localized recurrent lesions (called zoster) later in life, due to reactivation in the ganglia. The disease can be severe in immunocompromised patients such as AIDS patients or transplant recipients. The reference drug for the treatment of immunocompromised patients presenting with VZV infections and of patients presenting with zoster is acyclovir (ACV) (7). Recently, brivudine (BVDU), another nucleoside analog, has been marketed for the treatment of varicella and zoster (15,23).We have demonstrated that several members of a new class of antivirals, the bicyclic pyrimidine nucleoside analogues (BCNAs), are highly potent and selective inhibitors of VZV in vitro (3-5, 12, 13, 16-18). This new class of compounds exhibits exclusive specificity for VZV and obligatorily requires an alkyl or alkylaryl side chain at the furan moiety for potent anti-VZV activity.ACV-resistant VZV strains have been reported to emerge with increasing frequency in immunocompromised patients after long-term therapy with ACV (1). These observations justify drug sensitivity evaluation of resistant viral strains obtained after exposure to molecules belonging to different classes of antiviral agents.The present work demonstrates the exquisite antiviral activity of a selection of the most potent BCNAs against a broad range of clinical VZV isolates. These BCNA molecules were also investigated for their activity against VZV strains that were selected in the presence of several of the BCNAs, demonstrating that the BCNAs select for drug-resistant VZV phenotypes resulting from mutations in the virus-encoded thymidine kinase (TK).

Recently, an entirely new class of bicyclic nucleoside analogs (BCNAs) was found to display exquisite potency and selectivity as inhibitors of varicella-zoster virus (VZV) replication in cell culture. A striking difference in their ability to convert the BCNAs to their phosphorylated derivatives was observed between the VZV-encoded thymidine kinase (TK) and the very closely related herpes simplex virus type 1 (HSV-1) TK. Whereas VZV TK efficiently phosphorylated the BCNAs, HSV-1 TK was unable to do so. In addition, the thymidylate (dTMP) kinase activity of VZV TK further converted BCNA-5Ј-MP to BCNA-5Ј-DP. The BCNAs (or their phosphorylated derivatives) were not a substrate for cytosolic TK, mitochondrial TK, or cytosolic dTMP kinase. Human erythrocyte nucleoside diphosphate (NDP) kinase was unable to phosphorylate the BCNA 5Ј-diphosphates to BCNA 5Ј-triphosphates. Under the same experimental conditions, the anti-herpetic (E)-5-(2-bromovinyl)-2Ј-deoxyuridine (BVDU) derivative was efficiently converted to BVDU-MP and BVDU-DP by both VZV TK and HSV-1 TK and further, into BVDU-TP, by NDP kinase. Our observations may account for the unprecedented specificity of BCNAs as anti-VZV agents.