HIV-1 reverse transcriptase inhibitors.
Reverse transcriptase (RT) is one of the three enzymes encoded by the human immunodeficiency virus type 1 (HIV-1), the etiological agent of AIDS. Together with protease inhibitors, drugs inhibiting the RNA- and DNA-dependant DNA polymerase activity of RT are the major components of highly active antiretroviral therapy (HAART), which has dramatically reduced mortality and morbidity of people living with HIV-1/AIDS in developed countries. In this study, we focus on RT inhibitors approved by the US Food and Drugs Administration (FDA) or in phases II and III clinical trials. RT inhibitors belong to two main classes acting by distinct mechanisms. Nucleoside RT inhibitors (NRTIs) lack a 3' hydroxyl group on their ribose or ribose mimic moiety and thus act as chain terminators. Non-NRTIs bind into a hydrophobic pocket close to the polymerase active site and inhibit the chemical step of the polymerization reaction. For each class of inhibitors, we review the mechanism of action, the resistance mechanisms selected by the virus, and the side effects of the drugs. We also discuss the main perspectives for the development of new RT inhibitors.
El Safadi
Yazan
Y
Architecture et Réactivité de l'ARN, Université Louis Pasteur, CNRS, IBMC, 15 rue René Descartes, 67084, Strasbourg cedex, France.
Vivet-Boudou
Valérie
V
Marquet
Roland
R
D019380:Anti-HIV Agents / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002986:Clinical Trials as Topic; D017277:Drug Approval; D015195:Drug Design; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009705:Nucleosides / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D010766:Phosphorylation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity
D019380:Anti-HIV Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase