A Novel, Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase (Review)
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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).
KeywordsChain Terminator Bovine Kidney Cell Fresh Peripheral Blood Mononuclear Cell Photoaffinity Probe Incomplete Viral Inhibition
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- 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
- 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of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone, BI-RG-587, using a heteropolymeric template, Unpublished observations.Google Scholar
- 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
- 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
- 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
- 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
- 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
- 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