Search results for "Reverse Transcriptase Inhibitor"
showing 10 items of 50 documents
Increase in transmitted resistance to non-nucleoside reverse transcriptase inhibitors among newly diagnosed HIV-1 infections in Europe
2014
Background: One out of ten newly diagnosed patients in Europe was infected with a virus carrying a drug resistant mutation. We analysed the patterns over time for transmitted drug resistance mutations (TDRM) using data from the European Spread program.Methods: Clinical, epidemiological and virological data from 4317 patients newly diagnosed with HIV-1 infection between 2002 and 2007 were analysed. Patients were enrolled using a pre-defined sampling strategy.Results: The overall prevalence of TDRM in this period was 8.9% (95% CI: 8.1-9.8). Interestingly, significant changes over time in TDRM caused by the different drug classes were found. Whereas nucleoside resistance mutations remained con…
Lack of mitochondrial toxicity of darunavir, raltegravir and rilpivirine in neurons and hepatocytes: a comparison with efavirenz.
2014
Objectives Growing evidence associates the non-nucleoside reverse transcriptase inhibitor efavirenz with several adverse events. Newer antiretrovirals, such as the integrase inhibitor raltegravir, the non-nucleoside reverse transcriptase inhibitor rilpivirine and the protease inhibitor darunavir, claim to have a better toxicological profile than efavirenz while producing similar levels of efficacy and virological suppression. The objective of this study was to determine the in vitro toxicological profile of these three new antiretrovirals by evaluating their effects on the mitochondrial and cellular parameters altered by efavirenz in hepatocytes and neurons. Methods Hep3B cells and primary …
Efavirenz and the CNS: what we already know and questions that need to be answered
2015
The NNRTI efavirenz has long been one of the most frequently employed antiretroviral drugs in the multidrug regimens used to treat HIV infection, in accordance with its well-demonstrated antiretroviral efficacy and favourable pharmacokinetics. However, growing concern about its adverse effects has sometimes led to efavirenz being replaced by other drugs in the initial treatment selection or to switching of therapy to efavirenz-free regimens in experienced patients. Neurological and neuropsychiatric reactions are the manifestations most frequently experienced by efavirenz-treated patients and range from transitory effects, such as nightmares, dizziness, insomnia, nervousness and lack of conc…
Mitochondrial interference by anti-HIV drugs: mechanisms beyond Pol-γ inhibition.
2011
The combined pharmacological approach to the treatment of HIV infection, known as highly active antiretroviral therapy (HAART), has dramatically reduced AIDS-related morbidity and mortality. However, its use has been associated with serious adverse reactions, of which those resulting from mitochondrial dysfunction are particularly widespread. Nucleos(t)ide-reverse transcriptase inhibitors (NRTIs) have long been considered the main source of HAART-related mitochondrial toxicity due to their ability to inhibit Pol-γ, the DNA polymerase responsible for the synthesis of mitochondrial DNA. Nevertheless, accumulating evidence points to a more complex relationship between these organelles and NRTI…
Docking and multivariate methods to explore HIV-1 drug-resistance: a comparative analysis
2007
In this paper we describe a comparative analysis between multivariate and docking methods in the study of the drug resistance to the reverse transcriptase and the protease inhibitors. In our early papers we developed a simple but efficient method to evaluate the features of compounds that are less likely to trigger resistance or are effective against mutant HIV strains, using the multivariate statistical procedures PCA and DA. In the attempt to create a more solid background for the prediction of susceptibility or resistance, we carried out a comparative analysis between our previous multivariate approach and molecular docking study. The intent of this paper is not only to find further supp…
2-(2,6-Dihalophenyl)-3-(pyrimidin-2-yl)-1,3-thiazolidin-4-ones as non-nucleoside HIV-1 reverse transcriptase inhibitors.
2004
Several 1,3-thiazolidin-4-ones bearing a 2,6-dihalophenyl group at C-2 and a substituted pyrimidin-2-yl ring at the N-3 were synthesised and evaluated as anti-HIV agents. The results of the in vitro tests showed that some of them were highly effective inhibitors of human immunodeficiency virus type-1 (HIV-1) replication at 10–40 nM concentrations with minimal cytotoxicity. Structure–activity relationship studies revealed that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus had a significant impact on the in vitro anti-HIV activity of this class of potent antiretroviral agents. The compounds had significantly reduced activity against the characteristic N…
(2'-5')Oligoadenylate and intracellular immunity against retrovirus infection.
1992
1. 1. The double-stranded RNA-dependent 2′,5′-oligoadenylate (2–5A) synthetase/ribonuclease L (RNase L) system plays an essential role in the establishment of the antiviral state of a cell exposed to virus infection. 2. 2. Until recently, the application of 2–5A derivatives to reinforce this system seemed to be limited mainly due to the low specificity of RNase L for viral RNA. 3. 3. Two new strategies have been developed which yield a selective antiviral effect of 2–5As at least against human immunodeficiency virus-1 (HIV-1) infection: (i) an “intracellular immunization” appproach using 2-5A synthetase cDNA linked to HIV trans -acting response element (TAR) and (ii) inhibition of retrovira…
Binding isotope effects as a tool for distinguishing hydrophobic and hydrophilic binding sites of HIV-1 RT.
2014
The current treatment for HIV-1 infected patients consists of a cocktail of inhibitors, in an attempt to improve the potency of the drugs by adding the possible effects of each supplied compound. In this contribution, nine different inhibitors of HIV-1 RT, one of the three key proteins responsible for the virus replication, have been selected to develop and test a computational protocol that allows getting a deep insight into the inhibitors’ binding mechanism. The interaction between the inhibitors and the protein have been quantified by computing binding free energies through FEP calculations, while a more detailed characterization of the kind of inhibitor–protein interactions is based on …
Cordycepin analogues of 2',5'-oligoadenylate inhibit human immunodeficiency virus infection via inhibition of reverse transcriptase.
1991
Analogues of 2',5'-oligoadenylates (2-5A), the cordycepin (3'-deoxyadenosine) core trimer (Co3) and its 5'-monophosphate derivative (pCo3), were shown to display pronounced anti-human immunodeficiency virus type 1 (HIV-1) activity in vitro. Treatment of HIV-1 infected H9 cells with 1 microM Co3 or pCo3 resulted in an almost 100% inhibition of virus production. The compounds were encapsulated in liposomes targeted by antibodies specific for the T-cell receptor molecule CD3. Substitution of one or two cordycepin units in Co3 or pCo3 decreased the antiviral activity of the compounds. pCo3 did not stimulate 2-5A-dependent ribonuclease L activity and displayed no effect on the amount of cellular…
Theoretical studies of HIV-1 reverse transcriptase inhibition
2012
Computational methods for accurately calculating the binding affinity of a ligand for a protein play a pivotal role in rational drug design. We herein present a theoretical study of the binding of five different ligands to one of the proteins responsible for the human immunodeficiency virus type 1 (HIV-1) cycle replication; the HIV-1 reverse transcriptase (RT). Two types of approaches are used based on molecular dynamics (MD) simulations within hybrid QM/MM potentials: the alchemical free energy perturbation method, FEP, and the pathway method, in which the ligand is physically pulled away from the binding site, thus rendering a potential of mean force (PMF) for the binding process. Our com…