tipranavir and Acquired-Immunodeficiency-Syndrome

This review deals with clinical applications of compounds that inhibit the action of the protease encoded within the genome of human immunodeficiency virus (HIV). The HIV-protease is essential for viral maturation and represents an important therapeutic target in the fight against AIDS. Following a brief overview of the enzyme structure and function, the article focuses on a number of peptide and non-peptide based HIV-protease inhibitors that are in current clinical use. These drugs are discussed both with respect to their efficacy in treatment of AIDS, and to problems related to insurgence of viral resistance and side effects seen to date in patient populations.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Binding Sites; Carbamates; Clinical Trials as Topic; Computer-Aided Design; Crystallography, X-Ray; Drug Design; Drug Resistance, Microbial; Drug Therapy, Combination; Furans; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Oligopeptides; Pyridines; Pyrones; Randomized Controlled Trials as Topic; Ritonavir; Saquinavir; Sulfonamides

HIV infected patients often take at least three anti-HIV drugs together in Highly Active Antiretroviral Therapy (HAART) and/or Ritonavir-Boosted Protease Inhibitor Therapy (PI/r) to suppress the viral replications. The potential drug-drug interactions affect efficacy of anti-HIV treatment and major source of such interaction is competition for the drug metabolizing enzyme, cytochrome P450 (CYP). CYP3A4 isoform is the enzyme responsible for metabolism of currently available HIV-1 protease drugs. Hence administration of these drugs in HARRT or PI/r leads to increased toxicity and reduced efficacy in HIV treatment. We used computational molecular docking method to predict such interactions by which to compare experimentally measured metabolism of each HIV-1 protease drug. AutoDock 4.0 was used to carry out molecular docking of 10 HIV-protease drugs into CYP3A4 to explore sites of reaction and interaction energies (i.e., binding affinity) of the complexes. Arg105, Arg106, Ser119, Arg212, Ala370, Arg372, and Glu374 are identified as major drug binding residues, and consistent with previous data of site-directed mutagenesis, crystallography structure, modeling, and docking studies. In addition, our docking results suggested that phenylalanine clusters and heme are also participated in the binding to mediate drug oxidative metabolism. We have shown that HIV-1 protease drugs such as tipranavir, nelfinavir, lopinavir, and atazanavir differ in their binding modes on each other for metabolic clearance in CYP3A4, whereas ritonavir, amprenavir, indinavir, saquinavir, fosamprenavir, and darunavir share the same binding mode.

Topics: Acquired Immunodeficiency Syndrome; Antiretroviral Therapy, Highly Active; Computational Biology; Cytochrome P-450 CYP3A; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Lopinavir; Nelfinavir; Pyridines; Pyrimidinones; Pyrones; Ritonavir; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Darunavir; Drug Resistance, Multiple, Viral; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Mutation; Pyridines; Pyrimidinones; Pyrones; Sulfonamides

Topics: Acquired Immunodeficiency Syndrome; Drug Approval; HIV Protease Inhibitors; Humans; Pyridines; Pyrones; Sulfonamides; United States; United States Food and Drug Administration

Topics: Acquired Immunodeficiency Syndrome; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Viral; Drug Therapy, Combination; HIV Protease Inhibitors; HIV-1; Humans; Multicenter Studies as Topic; Pyridines; Pyrones; Randomized Controlled Trials as Topic; Sulfonamides; Virus Replication

Topics: Acquired Immunodeficiency Syndrome; Adenine; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Atazanavir Sulfate; Carbamates; Deoxycytidine; Dioxolanes; Drugs, Investigational; Emtricitabine; Furans; Guanosine; HIV Fusion Inhibitors; Humans; Imidazoles; Oligopeptides; Organophosphates; Organophosphonates; Organophosphorus Compounds; Prodrugs; Protease Inhibitors; Pyridines; Pyrones; Quinazolines; Reverse Transcriptase Inhibitors; Sulfonamides; Sulfur Compounds; Tenofovir