Advertisement

Antiretroviral Activity of Carbocyclic Nucleosides and Potential Use of Inosinate Dehydrogenase Inhibitors

  • Larry L. BondocJr.
  • Arnold Fridland
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)

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.

Keywords

Human Immunodeficiency Virus Human Immunodeficiency Virus Infectivity Antiviral Activity Nucleoside Analog Mycophenolic Acid 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    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).PubMedCrossRefGoogle Scholar
  2. 2.
    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).PubMedCrossRefGoogle Scholar
  3. 3.
    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).PubMedCrossRefGoogle Scholar
  4. 4.
    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).PubMedCrossRefGoogle Scholar
  5. 5.
    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).PubMedGoogle Scholar
  6. 6.
    W. R. A. Osborne, Kinase activities of T and B lymphoblasts distinguished by autoradiography. Proc. Natl. Acad. Sci. USA 83: 4030–34 (1986).PubMedCrossRefGoogle Scholar
  7. 7.
    M. C. Hurley, T. D. Patella, and I. H. Fox, Human placental deoxyadenosine and deoxyguanosine phosphorylating activity. J. Biol. Chem. 258: 15021–27 (1983).PubMedGoogle Scholar
  8. 8.
    J. C. Sarup and A. Fridland, Identification of purine deoxyribonucleoside kinases for human leukemia cells. Biochemistry 26: 590–97 (1987).PubMedCrossRefGoogle Scholar
  9. 9.
    M. A. Johnson and A. Fridland, Phosphorylation of 2’,3’dideoxyinosine by cytosolic 5’-nucleotidase. Mol. Pharmacol. 36: 291–95 (1989).PubMedGoogle Scholar
  10. 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. 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. 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

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Larry L. BondocJr.
    • 1
  • Arnold Fridland
    • 1
  1. 1.Department of Biochemical and Clinical PharmacologySt. Jude Children’s Research HospitalMemphisUSA

Personalised recommendations