title: Looking for an active conformation of the future HIV type-1 non-nucleoside reverse transcriptase inhibitors.
abstract: HIV type-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV infection. NNRTI-based HAART regimes effectively suppress viral reproduction, are not cytotoxic and show favourable pharmacokinetic properties. First-generation NNRTIs suffer the rapid selection of viral variants, hampering the binding of inhibitors into the reverse transcriptase (RT) non-nucleoside binding site (NNBS). Efforts to improve these first inhibitors led to the discovery of second-generation NNRTIs that proved to be effective against the drug-resistant mutant HIV-1 strains. The success of such agents launched a new season of NNRTI design and synthesis. This paper reviews the characteristics of second-generation NNRTIs, including etravirine, rilpivirine, RDEA-806, UK-453061, BIRL 355 BS, IDX 899, MK-4965 and HBY 097. In particular, the binding modes of these inhibitors into the NNBS of the HIV-1 RT and the most clinically relevant mutant RTs are analysed and discussed.
authors: Department of Chimica e Tecnologie del Farmaco, Istituto Pasteur - Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy.
authors: Giuseppe
authors: G
authors: La Regina
authors: Antonio
authors: A
authors: Coluccia
authors: Romano
authors: R
authors: Silvestri
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D023241:Antiretroviral Therapy, Highly Active; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D010721:Phosphinic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000068696:Rilpivirine
chemical_list: C532853:3-(5-((6-amino-1H-pyrazolo(3,4-b)pyridine-3-yl)methoxy)-2-chlorophenoxy)-5-chlorobenzonitrile; D019380:Anti-HIV Agents; C534138:IDX 899; D007211:Indoles; D009570:Nitriles; D010721:Phosphinic Acids; D011720:Pyrazoles; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D011810:Quinoxalines; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; C451734:etravirine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; D000068696:Rilpivirine; C093110:HBY 097