ABSTRACT
Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.
Subject(s)
Humans , Anti-HIV Agents/chemistry , Computer-Aided Design , Drug Design , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1 , Reverse Transcriptase Inhibitors/pharmacology , HIV Infections/drug therapy , HIV Reverse Transcriptase/chemistry , HIV-1 , Models, Biological , Molecular Structure , Quantitative Structure-Activity Relationship , Reverse Transcriptase Inhibitors/chemistryABSTRACT
A laccase with a molecular mass of 67 kDa and inhibitory activity toward HIV-1 reverse transcriptase (IC50 = 7.5 M) was isolated from fresh fruiting bodies of the Lentinus edodes (Shiitake mushroom). Its characteristics were compared with those of laccases from cultured mushroom mycelia reported earlier. The laccase was unadsorbed on DEAE-cellulose, Affi-gel blue gel and CM-cellulose, but was adsorbed on Con A-Sepharose. About 50-fold purification was achieved with a 19.2% yield of the enzyme. The activity of the enzyme increased steadily from 20°C to 70°C. The activity disappeared after exposure to the boiling temperature for 10 min. Its optimal pH was 4 and very little enzyme activity remained at and above pH 10. The laccase inhibited HIV-1 reverse transcriptase with an IC50 of 7.5 M, but did not demonstrate any antifungal or anti-proliferative activity.
Subject(s)
Amino Acid Sequence , Anti-HIV Agents/chemistry , Anti-HIV Agents/isolation & purification , Anti-HIV Agents/metabolism , Anti-HIV Agents/pharmacology , Fruiting Bodies, Fungal/enzymology , Fruiting Bodies, Fungal/growth & development , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/metabolism , HIV-1/enzymology , Hydrogen-Ion Concentration , Laccase/chemistry , Laccase/isolation & purification , Laccase/metabolism , Laccase/pharmacology , Molecular Weight , Mycelium/enzymology , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/isolation & purification , Reverse Transcriptase Inhibitors/metabolism , Reverse Transcriptase Inhibitors/pharmacology , Shiitake Mushrooms/enzymology , Shiitake Mushrooms/growth & development , Substrate Specificity , TemperatureABSTRACT
De los 25 anti-retrovirales disponibles en el mercado, sólo 16 están autorizados en la edad pediátrica. Los antiretrovirales, pertenecientes a las tres primeras familias, usados desde hace dos décadas, continúan vigentes y son parte importante de la terapia anti-retroviral en niños naïve. Se describen las dosis, presentaciones y asociaciones actuales de estos fármacos en la edad pediátrica y además se comentan las nuevas co-formulaciones que permitirán disminuir el número de dosis, mejorar la tolerancia y por lo tanto conseguir mejor adherencia de los pacientes pediátricos.
Of the 25 antiretroviral drugs available in the market, only 16 are allowed for prescription in the pediatric patients. The antiretroviral, pertaining to the first three families, used for two decades, remain valid and are important components of antiretroviral therapy in naive children. We describe doses, presentations and current associations for these drugs in children, and also discuss new co-formulations that will reduce the number of doses, improve tolerance and therefore achieve better adherence of pediatric patients.
Subject(s)
Child , Humans , Anti-Retroviral Agents/administration & dosage , HIV Infections/drug therapy , Acquired Immunodeficiency Syndrome/drug therapy , Anti-HIV Agents/administration & dosage , Drug Administration Schedule , HIV Protease Inhibitors/administration & dosage , HIV Reverse Transcriptase/antagonists & inhibitors , Reverse Transcriptase Inhibitors/administration & dosageABSTRACT
The present study evaluated the incidence and risk factors that correlated with the development of non-nucleoside reverse transcriptase inhibitor (NNRTI) related rash in 69 Thai children followed prospectively. The overall incidence of NNRTI-related rash was 16% (22% for NVP and 4% for EFV rash). The only significant predictive factor that correlated with the development of NNRTI-related rash in a multivariate logistic regression model was a CD4% decrease at week 12.
Subject(s)
Anti-HIV Agents/adverse effects , Anti-Retroviral Agents/adverse effects , CD4 Lymphocyte Count , Child , Child, Preschool , Exanthema/chemically induced , Female , HIV Reverse Transcriptase/antagonists & inhibitors , Humans , Male , Prospective Studies , Reverse Transcriptase Inhibitors/adverse effects , Risk Factors , Thailand/epidemiologyABSTRACT
Studies involving infectious, wild type HIV-1 must be performed under strict BSL-3 practice. We have employed a defective (deltaTat/Rev)MC99 and cloned 1A2 line, ie, mutated HIV-1 and Tat/Rev transfected cells to verify anti-HIV-1 activity in a BSL-2 laboratory. A number of extracts from various parts of 11 species of plants were studied. Results were correlated with those of an anti-HIV-1 reverse transcriptase (RT) assay.