Nucleoside Reverse Transcriptase Inhibitors

Nucleoside analogs were the first line of defense for the treatment of HIV infection in 1987 (36). Subsequent studies of various combination therapies of indinavir, zidovudine, and lamivudine led to the beginnings of general combination therapy and the refinement of HAART combination therapy. These early studies suggested that a prompt and aggressive drug therapy with three or more antiviral drugs from two or three classes of drugs might be more effective. HAART can reduce the plasma HIV virus levels to levels below the existing limits of detection (17).

Mechanisms of action. Nucleoside analogues are dideoxy-nucleoside analogues which are phosphorylated intracellu-larly into active triphosphate metabolites. The active form then competitively inhibits HIV reverse transcriptase by acting as an alternate substrate for the enzyme. This family of compounds lacks the 3'-hydroxyl group, which leads to chain termination once the active metabolite is incorporated into the developing DNA strand. Figure 2.2 depicts the site of action of the existing and new antiretroviral drugs.

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