Inhibitors of HIV-1 reverse transcriptase and integrase: classical and emerging therapeutical approaches. 2002

Laura Tarrago-Litvak, and Marie Line Andreola, and Michel Fournier, and Georgy A Nevinsky, and Vincent Parissi, and Vaea Richard de Soultrait, and Simon Litvak
UMR 5097 CNRS-Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux cedex, France. laura.litvak@reger.u-bordeaux.fr

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.

UI MeSH Term Description Entries
D009841 Oligonucleotides Polymers made up of a few (2-20) nucleotides. In molecular genetics, they refer to a short sequence synthesized to match a region where a mutation is known to occur, and then used as a probe (OLIGONUCLEOTIDE PROBES). (Dorland, 28th ed) Oligonucleotide
D004353 Drug Evaluation, Preclinical Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications. Drug Screening,Evaluation Studies, Drug, Pre-Clinical,Drug Evaluation Studies, Preclinical,Drug Evaluations, Preclinical,Evaluation Studies, Drug, Preclinical,Evaluation, Preclinical Drug,Evaluations, Preclinical Drug,Medicinal Plants Testing, Preclinical,Preclinical Drug Evaluation,Preclinical Drug Evaluations,Drug Screenings,Screening, Drug,Screenings, Drug
D004359 Drug Therapy, Combination Therapy with two or more separate preparations given for a combined effect. Combination Chemotherapy,Polychemotherapy,Chemotherapy, Combination,Combination Drug Therapy,Drug Polytherapy,Therapy, Combination Drug,Chemotherapies, Combination,Combination Chemotherapies,Combination Drug Therapies,Drug Polytherapies,Drug Therapies, Combination,Polychemotherapies,Polytherapies, Drug,Polytherapy, Drug,Therapies, Combination Drug
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000163 Acquired Immunodeficiency Syndrome An acquired defect of cellular immunity associated with infection by the human immunodeficiency virus (HIV), a CD4-positive T-lymphocyte count under 200 cells/microliter or less than 14% of total lymphocytes, and increased susceptibility to opportunistic infections and malignant neoplasms. Clinical manifestations also include emaciation (wasting) and dementia. These elements reflect criteria for AIDS as defined by the CDC in 1993. AIDS,Immunodeficiency Syndrome, Acquired,Immunologic Deficiency Syndrome, Acquired,Acquired Immune Deficiency Syndrome,Acquired Immuno-Deficiency Syndrome,Acquired Immuno Deficiency Syndrome,Acquired Immuno-Deficiency Syndromes,Acquired Immunodeficiency Syndromes,Immuno-Deficiency Syndrome, Acquired,Immuno-Deficiency Syndromes, Acquired,Immunodeficiency Syndromes, Acquired,Syndrome, Acquired Immuno-Deficiency,Syndrome, Acquired Immunodeficiency,Syndromes, Acquired Immuno-Deficiency,Syndromes, Acquired Immunodeficiency
D015195 Drug Design The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include PHARMACOKINETICS, dosage analysis, or drug administration analysis. Computer-Aided Drug Design,Computerized Drug Design,Drug Modeling,Pharmaceutical Design,Computer Aided Drug Design,Computer-Aided Drug Designs,Computerized Drug Designs,Design, Pharmaceutical,Drug Design, Computer-Aided,Drug Design, Computerized,Drug Designs,Drug Modelings,Pharmaceutical Designs
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D016914 Ribonuclease H A ribonuclease that specifically cleaves the RNA moiety of RNA:DNA hybrids. It has been isolated from a wide variety of prokaryotic and eukaryotic organisms as well as RETROVIRUSES. Endoribonuclease H,RNase H,Ribonuclease H, Calf Thymus,RNAase H
D054303 HIV Reverse Transcriptase A reverse transcriptase encoded by the POL GENE of HIV. It is a heterodimer of 66 kDa and 51 kDa subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse H activity (RIBONUCLEASE H, HUMAN IMMUNODEFICIENCY VIRUS) that plays an essential role the viral replication process. Reverse Transcriptase, HIV,Reverse Transcriptase, Human Immunodeficiency Virus,Transcriptase, HIV Reverse
D018894 Reverse Transcriptase Inhibitors Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. Reverse Transcriptase Inhibitor,Inhibitors, Reverse Transcriptase,Inhibitor, Reverse Transcriptase,Transcriptase Inhibitor, Reverse

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