The major objectives of this research are (a) to synthesize selected lipophilic prodrugs of the antiviral agent 9-Beta-D-arabinofuranosyladenine (araA) in large-scale amounts for in vivo chemotherapy experiments, (b) to continue to evaluate and optimize the most active araA prodrug formulations for therapeutic efficacy in the topical, oral, and topical + oral treatment of herpes simplex virus (HSV) type 1 cutaneous infections in hairless mice and HSV type 2 genital infections in guinea pigs, (c) to evaluate the most active candidate prodrugs, including araA-2 feet, 3 feet-diacetate (araADA), araA-2 feet-monoacetate (araAMA), and araA-5 feet-monobutyrate (araAMB), for efficacy in the treatment of recurrent genital herpes in guinea pigs and to determine the effects of these araA prodrugs on latent virus infections of the sensory ganglia in both hairless mice and guinea pigs, (d) to conduct in-depth studies of the effects of penetration enhancers such as AzoneTM on araA prodrug delivery to tissues, (e) to determine whether araAMA is itself phosphorylated and intrinsically active as an antiviral agent, (f) to attempt the sustained, site-specific targeting of araA prodrugs to the brain, CNS, and peripheral nervous tissue using N-alkyl-dihydropyridyl prodrug esters of candidate antiviral compounds in the treatment of herpes encephalitis in mice and recurrent genital herpes in guinea pigs, and (g) to conduct pharmacological studies to quantitatively measure antiviral drug levels in the blood, brain, ganglia, and other tissues after administration of araA prodrugs to laboratory animals. These studies may ultimately lead to the development of topically and orally effective araA derivatives for use in the successful treatment of oral and genital herpesvirus infections in man. The controlled release of selective antiviral drugs specifically in the brain, CNS, and other nervous tissues may result in the improvement of therapy for herpes encephalitis and in the possible control, if not cure, of recurrent herpetic disease.