Inhibitors of HIV-1 Reverse Transcriptase and Integrase: Classical and Emerging Therapeutical Approaches

The rapid spread of the AIDS epidemic has stimulated the search for new agents able to arrest the replication of the causative virus, HIV. The best strategy for AIDS treatment involves a combination therapy using inhibitors of reverse transcriptase and protease. However, the emergence of HIV-1 strains resistant to these drugs and their cytotoxicity requires the synthesis and the biochemical and cellular characterization of new antiviral drugs, as well as the development of newer strategies and viral targets. In addition to reverse transcriptase and protease, other retroviral enzymes acting in the replicative cycle of HIV-1 are potential targets for chemotherapeutic intervention. Like all retroviruses, HIV-1 requires the integration of the proviral double-stranded DNA, arising from the reverse transcription step, into the host chromosome for its efficient replication, maintenance of a stably infected state and productive infection. DNA integration is carried out by integrase so this enzyme represents a key area in developing new anti-retroviral therapy. Another novel enzymatic target concerns the RNase H activity associated with the retroviral reverse transcriptase, since a functional RNase H is essential for retroviral replication. Inhibitors against HIV-1 integrase and RNase H having potential therapeutical propeties have not yet been described. We focus this review on the properties of inhibitors of reverse transcriptase and integrase. Some of these antiviral agents have been known for several years while others are emerging as new promising strategies based on the use of oligonucleotides with special emphasis on the SELEX approach, peptides and retrovirucides.