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HIV Life Cycle

Reverse Transcription

Production of proviral DNA includes several possible targets for intervention. These include binding of the primer tRNA, production of DNA from RNA by reverse transcriptase (RT), degradation of viral RNA by the RNAse H domain of RT, and second strand DNA synthesis by RT. RT has been a prominent target in the discovery and development of therapies to suppress or prevent HIV infection and related diseases (1-2).

The first drug shown clinically effective and licensed for the treatment of HIV infection in humans (3'-azido-2',3'-dideoxythymidine [Zidovudine or AZT] (3-4) was initially tested for its potential as an antiviral compound in 1974 (5-6). Many pyrimidine and purine 2',3'-dideoxynucleoside (ddN) analogs have been shown to inhibit replication and the pathogenic effects of HIV-1 in cell cultures. Several nucleoside analogs are currently undergoing clinical evaluation.

Most nucleosides are progressively phosphorylated by cytoplasmic enzymes to nucleoside 5'-triphosphates that compete with the natural nucleoside triphosphate substrate for binding to cellular DNA polymerase and the viral RT(7-8). It is assumed that most nucleosides are incorporated into viral DNA and prevent the continued polymerization of the DNA chain due to the absence of a 3'-hydroxyl group. The termination of DNA chain synthesis results in prevention of viral replication (9).

Several reviews have been published on nucleoside analogs tested for anti-HIV activity (10-11).

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A series of non-nucleoside RT inhibitors structurally related to benzodiazepines (TIBO and BI-RG-587) (12-13) and a pyridinone derivative (14) are now undergoing clinical evaluation and candidates have been approved by the FDA for AIDS treatment. These non-nucleoside RT inhibitors bind to the same site on RT, are noncompetitive inhibitors, have high selectivity for HIV-1 and wide therapeutic indices in vitro. These compounds have little or no effect on RT from HIV-2 or SIV or on the replication of these viruses in cultured cells. In contrast to the ddNs, TIBO-related compounds appear to be significantly more effective in blocking RT activity when a natural template-primer substrate is used than when a synthetic template-primer pair is utilized (13).

References

1. Mitsuya, H., Broder, S. Inhibition of the in vitro infectivity and cytopathic effects of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3' -dideoxynucleosides. Proc Natl Acad Sci USA, 1986; 83:1911-1915.

2. Mitsuya, H., Broder, S. Strategies for antiviral therapy in AIDS. Nature (London) 1987; 325:773-778.

3. Mitsuya, H., Weinhold, K.J., Furman, P.A., et al. 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 USA, 1985; 82:7096-7100.

4. Fischl, M.A., Richman, D.D., Grieco, M.H., et al. 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; 317:185.

5. Ostertag, W., Roesler, G., Krieg, C.J., et al. Induction of endogenous virus and of thymidine kinase by bromodeoxyuridine in cell cultures transformed by Friend virus. Proc Natl Acad Sci USA 1974; 71:4980-4985.

6. Dube, S.K., Pragnell, I.B., Kluge, N., et al. Induction of endogenous and of spleen focus-forming viruses during dimethylsulfoxide-induced differentiation of mouse erythroleukemia cells transformed by spleen focus-forming virus. Proc Natl Acad Sci USA, 1975; 72:1863.

7. Ahluwalia, G., Cooney, D.A., Mitsuya, H., et al. Initial studies on the cellular pharmacology of 2',3'-dideoxyinosine, an inhibitor of HIV infectivity. Biochem Pharmacol 1987; 36:3797-3800.

8. Maag, H., Chu, N., Crawford-Ruth, D., Eugui, E., McRoberts, M.J., Mirkovich, A., Pettibone, M., Prisbe, E.J., Rydzewski, R.M., and Verheydin J.P.H. 4'-Azidothymidine: synthesis and in vitro anti-HIV activity. Antiviral Research Suppl April 1:43.

9. Belleau, B., Dixit, D., Ngueyen-Ba, N. and Kraus, J.L. Design and activity of a novel class of nucleoside analogs effective against HIV-1. Abstracts of papers, V International Conference on AIDS, Montreal, Canada, June 1989; European Patent Number 90301335.7, 1990 .

10. Nasr, M., Litterst, C., McGowan, J. Computer-assisted structure-activity correlations of dideoxynucleoside analogs as potential anti-HIV drugs. Antiviral Res, 1990; 14:125-148.

11. Broder, S. Clinical applications of 3'-azido-2', 3'-dideoxythymidine (AZT) and related dideoxynucleosides. Med Res Rev 1990; 10:419.

12. Merluzzi, V.J., Hardgrave, K.D., Labadia, M., et al. Inhibition of HIV-1 replication by a non-nucleoside reverse transcriptase inhibitor. Science 1990; 250:1411-1413.

13. Pauwels, R., Andries, K., Desmyter, J., et al. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature (London) 1990; 343:470-474.

14. Goldman, M.E., Obrien, J.A., Ruffing, T.L., Stern, A.M., Gaul, S.L., Saari, W.S., Wai, J.S., Hoffman, J., Rooney, C.S., Quintero, J.C., Schleif, W.A., Emini, E.A., and Nunberg, J.H. 7th International Conference on AIDS, Florence, June 16-21, 1991 , TU.A.67, p. 74.





  
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