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).
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
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.
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.
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.
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of HIV-1 reverse transcriptase by a non-nucleoside dipyridodiazepinone, BI-RG-587, using a heteropolymeric template, Unpublished observations.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1992 Springer Science+Business Media New York
About this chapter
Cite this chapter
Merluzzi, V.J., Rosenthal, A.S. (1992). A Novel, Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase (Review). In: Block, T.M., Jungkind, D., Crowell, R.L., Denison, M., Walsh, L.R. (eds) Innovations in Antiviral Development and the Detection of Virus Infections. Advances in Experimental Medicine and Biology, vol 312. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-3462-4_8
Download citation
DOI: https://doi.org/10.1007/978-1-4615-3462-4_8
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-6533-4
Online ISBN: 978-1-4615-3462-4
eBook Packages: Springer Book Archive