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. 1990 Aug;34(8):1505–1507. doi: 10.1128/aac.34.8.1505

Direct comparisons of inhibitor sensitivities of reverse transcriptases from feline and human immunodeficiency viruses.

T W North 1, R C Cronn 1, K M Remington 1, R T Tandberg 1
PMCID: PMC171861  PMID: 1699491

Abstract

The sensitivities of reverse transcriptases (RTs) from feline immunodeficiency virus (FIV) and human immunodeficiency virus type 1 (HIV) were directly compared. The two enzymes had similar sensitivities to three analogs of dTTP, namely, 3'-azido-3'-deoxythymidine 5'-triphosphate, 2',3'-dideoxythymidine 5'-triphosphate, and 2',3'-dideoxy-2',3'-didehydrothymidine 5'-triphosphate. Each of these analogs demonstrated competitive inhibition of both enzymes. Ki values for inhibition of FIV RT by these three inhibitors were 3.3, 6.7, and 1.8 nM, respectively; Ki values for inhibition of the HIV enzyme were 6.5, 5.9, and 8.3 nM, respectively. Ratios of the Ki for the inhibitor to the Km for the substrate were also determined for each inhibitor, and no differences between the two enzymes greater than threefold were observed. Inhibition constants for 3'-amino-3'-deoxythymidine 5'-triphosphate and 3'-fluoro-3'-deoxythymidine 5'-triphosphate were determined for FIV RT, and these were similar to published values for HIV RT. The activities of three dideoxynucleoside 5'-triphosphates against FIV RT were determined; ddGTP was slightly more potent than ddTTP, whereas both were much more effective than ddCTP. The activity of a noncompetitive inhibitor, phosphonoformate, was also examined with the FIV enzyme; it was much more active with poly(rA)-oligo(dT) as the template-primer than with poly(rC)-oligo(dG) or poly(rI)-oligo(dC).

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baba M., Pauwels R., Herdewijn P., De Clercq E., Desmyter J., Vandeputte M. Both 2',3'-dideoxythymidine and its 2',3'-unsaturated derivative (2',3'-dideoxythymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro. Biochem Biophys Res Commun. 1987 Jan 15;142(1):128–134. doi: 10.1016/0006-291x(87)90460-8. [DOI] [PubMed] [Google Scholar]
  2. Chen M. S., Oshana S. C. Inhibition of HIV reverse transcriptase by 2',3'-dideoxynucleoside triphosphates. Biochem Pharmacol. 1987 Dec 15;36(24):4361–4362. doi: 10.1016/0006-2952(87)90685-x. [DOI] [PubMed] [Google Scholar]
  3. Cheng Y. C., Dutschman G. E., Bastow K. F., Sarngadharan M. G., Ting R. Y. Human immunodeficiency virus reverse transcriptase. General properties and its interactions with nucleoside triphosphate analogs. J Biol Chem. 1987 Feb 15;262(5):2187–2189. [PubMed] [Google Scholar]
  4. Fischl M. A., Richman D. D., Grieco M. H., Gottlieb M. S., Volberding P. A., Laskin O. L., Leedom J. M., Groopman J. E., Mildvan D., Schooley R. T. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med. 1987 Jul 23;317(4):185–191. doi: 10.1056/NEJM198707233170401. [DOI] [PubMed] [Google Scholar]
  5. Gardner M. B., Luciw P. A. Animal models of AIDS. FASEB J. 1989 Dec;3(14):2593–2606. doi: 10.1096/fasebj.3.14.2556312. [DOI] [PubMed] [Google Scholar]
  6. Hamamoto Y., Nakashima H., Matsui T., Matsuda A., Ueda T., Yamamoto N. Inhibitory effect of 2',3'-didehydro-2',3'-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus. Antimicrob Agents Chemother. 1987 Jun;31(6):907–910. doi: 10.1128/aac.31.6.907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hizi A., McGill C., Hughes S. H. Expression of soluble, enzymatically active, human immunodeficiency virus reverse transcriptase in Escherichia coli and analysis of mutants. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1218–1222. doi: 10.1073/pnas.85.4.1218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lin T. S., Schinazi R. F., Prusoff W. H. Potent and selective in vitro activity of 3'-deoxythymidin-2'-ene (3'-deoxy-2',3'-didehydrothymidine) against human immunodeficiency virus. Biochem Pharmacol. 1987 Sep 1;36(17):2713–2718. doi: 10.1016/0006-2952(87)90253-x. [DOI] [PubMed] [Google Scholar]
  9. Mansuri M. M., Starrett J. E., Jr, Ghazzouli I., Hitchcock M. J., Sterzycki R. Z., Brankovan V., Lin T. S., August E. M., Prusoff W. H., Sommadossi J. P. 1-(2,3-Dideoxy-beta-D-glycero-pent-2-enofuranosyl)thymine. A highly potent and selective anti-HIV agent. J Med Chem. 1989 Feb;32(2):461–466. doi: 10.1021/jm00122a029. [DOI] [PubMed] [Google Scholar]
  10. Mitsuya H., Weinhold K. J., Furman P. A., St Clair M. H., Lehrman S. N., Gallo R. C., Bolognesi D., Barry D. W., Broder S. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc Natl Acad Sci U S A. 1985 Oct;82(20):7096–7100. doi: 10.1073/pnas.82.20.7096. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. North T. W., Cronn R. C., Remington K. M., Tandberg R. T., Judd R. C. Characterization of reverse transcriptase from feline immunodeficiency virus. J Biol Chem. 1990 Mar 25;265(9):5121–5128. [PubMed] [Google Scholar]
  12. North T. W., North G. L., Pedersen N. C. Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome. Antimicrob Agents Chemother. 1989 Jun;33(6):915–919. doi: 10.1128/aac.33.6.915. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Pedersen N. C., Ho E. W., Brown M. L., Yamamoto J. K. Isolation of a T-lymphotropic virus from domestic cats with an immunodeficiency-like syndrome. Science. 1987 Feb 13;235(4790):790–793. doi: 10.1126/science.3643650. [DOI] [PubMed] [Google Scholar]
  14. Schinazi R. F., Eriksson B. F., Hughes S. H. Comparison of inhibitory activities of various antiretroviral agents against particle-derived and recombinant human immunodeficiency virus type 1 reverse transcriptases. Antimicrob Agents Chemother. 1989 Jan;33(1):115–117. doi: 10.1128/aac.33.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Take Y., Inouye Y., Nakamura S., Allaudeen H. S., Kubo A. Comparative studies of the inhibitory properties of antibiotics on human immunodeficiency virus and avian myeloblastosis virus reverse transcriptases and cellular DNA polymerases. J Antibiot (Tokyo) 1989 Jan;42(1):107–115. doi: 10.7164/antibiotics.42.107. [DOI] [PubMed] [Google Scholar]
  16. Vrang L., Oberg B. PPi analogs as inhibitors of human T-lymphotropic virus type III reverse transcriptase. Antimicrob Agents Chemother. 1986 May;29(5):867–872. doi: 10.1128/aac.29.5.867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Yamamoto J. K., Sparger E., Ho E. W., Andersen P. R., O'Connor T. P., Mandell C. P., Lowenstine L., Munn R., Pedersen N. C. Pathogenesis of experimentally induced feline immunodeficiency virus infection in cats. Am J Vet Res. 1988 Aug;49(8):1246–1258. [PubMed] [Google Scholar]

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