Inhibitors of Reverse Transcriptase Zidovudine and Homologs

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The advent of AIDS and of human cancers caused by other retroviruses quickened interest in the search for inhibitors of the crucial retroviral enzyme, reverse transcriptase (RT). Reverse transcriptase is a complex molecule carrying at least four different enzyme activities: reverse transcriptase, DNA polymerase, ribonuclease H, and ribonuclease D. The first compound to display sufficient antiviral activity in r>iuo to be licensed for human use was 3'-azido-2',3'-dideoxythymidme, otherwise known as azidothymidine, AZT, or zidovudine (Fig. 16-1).

AZT is phosphorylated by cellular kinases to AZT triphosphate (AZT-PPP), which exerts its antiviral effect against HIV by the following mechanisms. AZT-PPP inhibits HIV reverse transcriptase, being accepted by the

- enzyme in preference to TTP. AZT-PPP binds to RT approximately 100 times more efficiently than it does to the cellular DNA polymerase a. AZT-PPP is incorporated into the growing HIV DNA chain, leading to premature chain termination. In addition, AZT monophosphate (AZT-P) competes successfully for the enzyme thymidylate kinase, resulting in depletion of the intracellular pool of TTP. Clearly, since the HIV provirus persists indefinitely in nondividing cells, it cannot possibly be expected that zidovudine administered to already infected people could do more than suppress replication; it could never eliminate the viral genome from the body.

Zidovudine is rapidly absorbed following oral administration and rather rapidly metabolized by hepatic glucuronidation (half-life about 1 hour) so that the drug needs to be given 2 or 3 times daily. Very ill hospitalized patients may be treated by continuous intravenous infusion. Side effects of zidovudine are frequent. The most important result Irom the toxicity of the drug for bone marrow, namely, macrocytic anemia (often requiring red cell transfusions) and granulocytopenia (neutropenia). Headache, nausea, and insomnia are common, and many patients develop a myopathy resulting in (reversible) wasting of proximal muscle groups. Severe side effects may demand suspension of treatment, reduction in the daily dosage, combined therapy with another nucleoside analog or interferon a or another cytokine displaying synergism, or replacement or alternation with another drug.

Early clinical trials in 1986 indicated that after several weeks of treatment with zidovudine advanced AIDS patients survived longer, experienced fewer and less severe opportunistic infections, temporarily regained helper T cells and DTH capability, displayed reduced levels of HIV core antigen (p24) in the blood, and generally felt better, as measured on the Karnofsky scale of well-being. However, progress of the disease is not arrested, and life expectancy is generally extended for only a year or two. The tendency now is to institute therapy much earlier, even prophylactically in seropositive individuals before symptoms become apparent, with a view to continuing medication for life. This raises major problems of (1) long-term toxicity and (2) emergence of drug-resistant mutants.

Resistance to zidovudine arises regardless of the regime employed. Mutations tend to occur in particular codons of the RT gene, resistance increasing as mutations accumulate over many months. Following withdrawal of the drug, AZT-resistant mutants tend to be replaced by susceptible virus. Cloned wild-type and mutant RT can be used to measure the binding affinity of various drugs, while the recent elucidation ol the structure of RT by X-ray crystallography should enable further inhibitors to be designed to act not only against the RT domain but also against the ribonuclease H and other domains of the enzyme complex

Other dideoxynucleosides, such as dideoxycytidine (ddC) and dideox-yinosine (ddl), do not show cross-resistance with AZT, nor do several different types of nonnucleoside inhibitors, such as the "TIBO" compounds that block HIV RT activities in different ways. Hence, the probability of emergence of drug resistance can be minimized by (1) combined chemotherapy or (2) alternating courses of different drugs, for example, AZT with ddC or interferon a. This regimen also alleviates the problem that the principal serious side effect of prolonged AZT usage is bone marrow toxicity, whereas ddl and ddC tend rather to cause peripheral neuropathy. Further details about the chemoprophylaxis and chemotherapy of AIDS with AZT and other drugs are given in Chapter 35.

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