Antiretroviral Activity of Carbocyclic Nucleosides and Potential Use of Inosinate Dehydrogenase Inhibitors
Analogs of nucleosides and nucleotides are currently receiving increased attention for the treatment of human immunodeficiency virus-induced diseases. Zidovudine (AZT), an inhibitor of the activity of reverse transcriptase of human immunodeficiency virus (HIV), is presently the only approved drug available for the treatment of AIDS. Significant dose-related toxicity has been associated with the administration of AZT to patients with AIDS. Anemia and neutropenia are the most common toxicities observed in such patients and may result in dose reductions or discontinuation of treatment (1,2). Several new compounds are being evaluated both clinically and experimentally as potential therapeutic agents against HIV infectivity (3). The purpose of this paper is to provide some background information on the activity and metabolism of a new carbocyclic guanosine nucleoside analog carbovir (carbocyclic 2′,3′-dideoxy-2′,3′-didehydroguanosine, NSC-614846) leading up to the interaction of such compound with inhibitors of the rate-limiting enzyme IMP dehydrogenase of guanine nucleotide metabolism.
KeywordsHuman Immunodeficiency Virus Human Immunodeficiency Virus Infectivity Antiviral Activity Nucleoside Analog Mycophenolic Acid
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- 10.M. Baba, R. Pauwels, J. Balzarini, P. Herdewijn, et al., Ribavirin antagonozes the inhibitory effects of pyrimidine dideoxynucleosides but enhances the inhibitory effects of purine dideoxynucleosides on replication of human immunodeficiency virus. Antimicrob. Agents Chemother. 31: 1613–17 (1987).PubMedGoogle Scholar
- 11.G. Ahluwalia, D. A. Cooney, L. L. Bondoc, M. J. Currens, et al., Inhibitors of IMP dehydrogenase stimulate the phosphorylation of the antiviral nucleoside 2’,3’-dideoxyguanosine. Biochem. Biophys. Res. Commun. (1990) (in press).Google Scholar
- 12.M. W. Vogt, K. L. Hartshorn, P. A. Furman, T. C. Chou, J. A. Fyfe, L. A. Coleman, C. Crumpacker, R. T. Schooley, and M. S. Hirsch, Ribavirin antagonizes the effect of Azidothymídine on HIV replication. Science 235: 1376–80 (1987).Google Scholar