Abstract
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.
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References
M. A. Fischl, D. D. Richman, M. H. Grieco, P. A., Gottlieb, et al., The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N. Engl. J. Med. 317: 185–91 (1987).
D. D. Richman, M. A. Fischi, M. H. Grieco, P. A. Gottlieb, et al., The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N. Engl. J. Med. 317: 192–97 (1987).
R. Yarchoan, H. Mitsuya, C. E. Myers, and S. Broder, Clinical pharmacology of 3’-azidothymidine (zidovudine) and related dideoxynucleosides. N. Engl. J. Med. 321: 726–38 (1989).
R. Vince, M. Hua, J. Brownell, S. Deluge, et al., Potent and selective activity of a new carbocyclic nucleoside analog (Carbovir) against human immunodeficiency virus in vitro. Biochem. Biophys. Res. Commun. 156: 1046–53 (1988).
Z. Hao, D. A. Cooney, N. R. Hartman, C. F. Perno, et al., Factors determining the activityof 2’,3’-dideoxynucleosides in suppressing human immunodeficiency virus in vitro. Mol. Pharmacol. 34: 431–35 (1988).
W. R. A. Osborne, Kinase activities of T and B lymphoblasts distinguished by autoradiography. Proc. Natl. Acad. Sci. USA 83: 4030–34 (1986).
M. C. Hurley, T. D. Patella, and I. H. Fox, Human placental deoxyadenosine and deoxyguanosine phosphorylating activity. J. Biol. Chem. 258: 15021–27 (1983).
J. C. Sarup and A. Fridland, Identification of purine deoxyribonucleoside kinases for human leukemia cells. Biochemistry 26: 590–97 (1987).
M. A. Johnson and A. Fridland, Phosphorylation of 2’,3’dideoxyinosine by cytosolic 5’-nucleotidase. Mol. Pharmacol. 36: 291–95 (1989).
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).
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).
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).
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© 1991 Plenum Press, New York
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Bondoc, L.L., Fridland, A. (1991). Antiretroviral Activity of Carbocyclic Nucleosides and Potential Use of Inosinate Dehydrogenase Inhibitors. In: Kumar, A. (eds) Advances in Molecular Biology and Targeted Treatment for AIDS. GWUMC Department of Biochemistry Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5928-9_29
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DOI: https://doi.org/10.1007/978-1-4684-5928-9_29
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