A Novel, Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase (Review)

  • Vincent J. Merluzzi
  • Alan S. Rosenthal
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 312)

Abstract

Human immunodeficiency virus type 1 (HIV-1) is the retrovirus responsible for the majority (>95%) of the acquired immunodeficiency syndrome (AIDS) cases in the world. The complicated life-cycle of this virus presents many challenging areas for intervention. Our laboratories have concentrated on prevention of the early phase in proviral synthesis, specifically interruption of the RNA > DNA metabolic process by interfering with the viral enzyme, reverse transcriptase (RT). The RT of HIV-1 is a necessary component for early proviral synthesis. This enzyme has binding sites for nucleoside triphosphates, template primer and a catalytic site for the polymerase reaction. Nucleotides are added to the polymerizing chain to create a complementary DNA molecule (for review see Gilboa et al., 1979). The most effective inhibitors of RT have been the nucleoside analogs which are converted to triphosphates by cellular enzymes and act as chain terminators of the RT reaction (Mitsuya et al., 1985). Zidovudine (3’-azido-2’-3’dideoxy-thymidine, AZT) has been shown to be of benefit in HIV-1 infected individuals (Yarchoan et al., 1986). However, there are side-effects associated with the use of AZT (Richman et al., 1987), in addition to incomplete viral inhibition (Ho et al., 1989) and viral resistance (Larder et al. 1989).

Keywords

Chain Terminator Bovine Kidney Cell Fresh Peripheral Blood Mononuclear Cell Photoaffinity Probe Incomplete Viral Inhibition 
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.

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References

  1. Gilboa, E., Mitra, S.W., Goff, S., and Baltimore, D., 1979, A detailed model of reverse transcription and tests of crucial aspects, Cell, 18:93–100.CrossRefPubMedGoogle Scholar
  2. Ho, D.D., Moudgil, T., and Alam, M., 1989, Quantitation of human immunodeficiency virus type I in the blood of infected persons, New. Eng. J. of Med., 321:1621–1625.CrossRefGoogle Scholar
  3. Hargrave, K.D., Hehnke, M.L., Cullen, E., Engel, W.W., Fuchs, V., Grozinger, K.G., Kapadia, S.R., Klunder, J.M., Mauldin, S., McNeil, D., Pal, K., Patel, U., Proudfoot, J.R., Rose, J., Schmidt, G., Skiles, J.W., Skoog, M., Vitous, J., and Adams, J., 1991, Novel Non-nucleoside inhibitors of HIV-1 reverse transcriptase. I. Tricyclic Benzopyrido-and Dipyridodiazepinones, J. Med. Chem., 34:2231–2241.CrossRefPubMedGoogle Scholar
  4. Kopp, E.B., Miglietta, J.J., Shrutkowski, A.G., Shih, C.K., Grob, P.M., and Skoog, M.T., 1991, Steady state kinetics and inhibition of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone, BI-RG-587, using a heteropolymeric template, Unpublished observations.Google Scholar
  5. Koup, R.A., Merluzzi, V.J., Hargrave, K.D., Adams, J., Grozinger, K., Eckner, R.J., and Sullivan, J.L., 1991, Inhibition of HIV-1 replication by the dipyridodiazepinone, BI-RG-587, J. Infec. Dis., 163:966–970.CrossRefGoogle Scholar
  6. Larder, B.A., Darby, G., and Richman, D.D., 1989, HIV with reduced sensitivity to Zidovudine (AZT) isolated during prolonged therapy, Science, 243:1731–1734.CrossRefPubMedGoogle Scholar
  7. Merluzzi, V.J., Hargrave, K.D., Labadia, M., Grozinger, K., Skoog, M., Wu, J., Shih, Cheng-Kon, Eckner, K., Hattox, S., Adams, J., Rosenthal, A.S., Faanes, R., Eckner, R.J., Koup, R.A., and Sullivan, J.L., 1990, Inhibition of HIV-1 replication by a non-nucleoside reverse transcriptase inhibitor, Science, 250:1411–1413.CrossRefPubMedGoogle Scholar
  8. Merluzzi, V.J., Faanes, R.B., Richman, D., and Moore, M.A.S., Comparison of BIRG-587 and Zidovudine on Human Bone Marrow Progenitors, 1991, Unpublished observations.Google Scholar
  9. Mitsuya, H., Weinhold, K.J., Furman, P.A., St. Clair, M.H., Nusinoff-Lehrman, S., Gallo, R.C., Bolognesi, D., Barry, D.W., and Broder, S., 1985, 3’Azido3’deoxythymidine (BWA509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphocyte virus type III/lymphadenopathyassociated virus in vitro, Proc. Natl. Acad. Sci., 82:7096–7100.CrossRefPubMedGoogle Scholar
  10. Richman, D.D., Fischl, M.A., Grieco, M.H., Gottlieb, M.S., Volberding, P.A., Laskin, O.L., Leedom, J.M., Groopman, J.E., Mildvan, D., Hirsch, M.S., Jackson, G.G., Durack, D.T., Nusinoff-Lehrman, S., and The AZT Collaborative Working Group, 1987, The toxicity of azidothymidine (AZT)in the treatment of patients with AIDS and AIDS-related complex, New Eng. J. of Med., 317:192–197.CrossRefGoogle Scholar
  11. Richman, D., Rosenthal, A.S., Skoog, M., Eckner, R.J., Chou, T.C., Sabo, J.P., and Merluzzi, V.J., 1991, BI-RG-587 is active against Zidovudine-resistant human immunodeficiency virus type 1 and synergistic with Zidovudine, Antimicrob. Agents and Chemother., 35:305–308.CrossRefGoogle Scholar
  12. Wu, J.C., Warren, T.C., Adams, J., Proudfoot, J., Skiles, J., Raghavan, P., Perry, C., Potocki, I., Farina, P.R., and Grob, P.M., 1991; A novel dipyridodiazepinone inhibitor of HIV-1 reverse transcriptase acts through a non-substrate binding site, Biochemistry, 30:2022–2026.CrossRefPubMedGoogle Scholar
  13. Yarchoan, R., Klecker, R.W., Weinhold, K.J., Markham, P.D., Lyerly, H.K., Durack, D.T., Gelman, E., Lehrman, S.N., Blum, R.M., Barry, D.W., Shearer, G.M., Fischl, M., Mitsuya, H., Gallo, R.C., Collins, J., Bolognesi, D., Myers, C., and Broder, S., 1986, Administration of 3’-azido-3’deoxy-thymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex, Lancet, 1:575–580.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Vincent J. Merluzzi
    • 1
  • Alan S. Rosenthal
    • 1
  1. 1.Boehringer Ingelheim Pharmaceuticals, Inc.RidgefieldUSA

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