366 Combination studies involving entecavir and HIV nucleoside reverse transcriptase inhibitors showed no antagonistic effects on HBV or HIV activity in vitro

2004 ◽  
Vol 40 ◽  
pp. 110 ◽  
Author(s):  
R. Colonno ◽  
L. Discotto ◽  
Y.F. Gong ◽  
B. Kimmel ◽  
S. Weinheimer
Keyword(s):  
Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Antagonistic Effects ◽  
Combination Studies

Insights into Biophysical Methods to Study Interactions Between HIV-1 Reverse Transcriptase and Non-nucleoside Reverse Transcriptase Inhibitors

2020 ◽  
Vol 17 (6) ◽  
pp. 818-825
Author(s):  
Julien Dumond ◽  
Jean-Marcel Julien Tronchet ◽  
Serge Kirkiacharian ◽  
Michel Seman ◽  
Michèle Reboud-Ravaux
Keyword(s):  
Reverse Transcriptase ◽  
Biological Effects ◽  
Tryptophan Fluorescence ◽  
Plasmonic Resonance ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Surface Plasmonic Resonance ◽  
Rt Inhibitors ◽  
Hiv 1

Background: Reverse Transcriptase (RT) of immunodeficiency virus type-1 (HIV-1) remains an essential target for new antiretroviral therapies. Non-nucleoside reverse transcriptase inhibitors (or NNRTIs) constitute a major class of RT inhibitors whose characterization is essential. Introduction: Several biochemical, biological, and biophysical methods have been previously used to analyze the biological effects of NNRTIs. We explored here the use of surface plasmonic resonance to characterize the affinity of RT towards selected NNRTIs and compared the results with those obtained with in vitro and in cellulo assays. Methods: The solubility and stability in buffers of the tested NNRTIs were assessed by spectrophotometry and fluorescence. Surface plasmonic resonance experiments to study direct NNRTIs binding to immobilized RT and intramolecular quenching of RT tryptophan fluorescence were used to determine the KA association constants (= 1/KD) between RT and the inhibitors. The in vitro inhibition constants of RT were determined using kinetics and the effects on three other potential targets (proteasome, HIV-1 integrase, and HIV-1 protease) were analyzed. Results: The results obtained with two typical molecules belonging to our previous N-hydroxyureido acylnucleoside derivatives series using the above biophysical assays matched those obtained in in vitro and previous in cellulo assays. Conclusion: Surface plasmonic resonance provides reliable thermodynamic information on the interaction of RT with NNRTIs and appears as a useful method for understanding their inhibitory mechanism.

HIV-1 Resistance Profile of the Novel Nucleoside Reverse Transcriptase Inhibitor β-D-2′,3′-Dideoxy-2′,3′-Didehydro-5-Fluorocytidine (Reverset™)

2003 ◽  
Vol 14 (1) ◽  
pp. 49-59 ◽  
Author(s):  
Romas Geleziunas ◽  
Karen Gallagher ◽  
Hangchun Zhang ◽  
Lee Bacheler ◽  
Sena Garber ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Highly Active Antiretroviral Therapy ◽  
Resistance Mutations ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Resistance Profile ◽  
Wide Range ◽  
Resistant Strains ◽  
Hiv 1

Nucleoside reverse transcriptase inhibitors (NRTIs) represent the cornerstone of highly active antiretroviral therapy when combined with non-nucleoside reverse transcriptase inhibitors (NNRTIs) or HIV-1 protease inhibitors (PIs). Unlike the NNRTIs and PIs, NRTIs must be successively phosphorylated by cellular kinases to a triphosphate form, which represents the active metabolite possessing antiviral activity. Emergence of viral resistance to NRTIs has severely hampered treatment options for persons infected with HIV-1. As such, there is an urgent need to develop NRTIs capable of suppressing NRTI-resistant strains of HIV-1. We have recently reported that the cytidine analogue D-d4FC (DPC817, Reverset™) effectively inhibits clinically prevalent resistant strains of HIV-1. In this report, we have extended these findings and now describe a detailed resistance profile for this novel NRTI. By examining a panel of 50 viruses carrying RTs derived from HIV-1 clinical isolates displaying a wide range of NRTI resistance mutations, we report that the median fold increase in effective antiviral concentration for such a panel of viruses is 3.2, which is comparable to tenofovir (2.8-fold) and didanosine (2.4-fold). D-d4FC is highly effective at inhibiting subsets of lamivudine-and zidovudine-resistant variants but, like other NRTIs, seems less potent against multi-NRTI-resistant viruses, particularly those carrying the Q151M complex of mutations. Finally, in vitro selections for HIV-1 mutants capable of replicating in the presence of D-d4FC yielded a mutant carrying the RT K65R mutation. This mutation confers 5.3- to 8.7-fold resistance to D-d4FC in vitro. These findings suggest that D-d4FC may represent an alternative NRTI for the treatment of individuals infected with lamivudine- and zidovudine-resistant strains of HIV-1.

The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro

AIDS ◽  
2004 ◽  
Vol 18 (16) ◽  
pp. 2127-2136 ◽  
Author(s):  
Martine Caron ◽  
Martine Auclair ◽  
Claire Lagathu ◽  
Anne Lombès ◽  
Ulrich A Walker ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Hiv 1

scholarly journals Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors

2002 ◽  
Vol 46 (3) ◽  
pp. 716-723 ◽  
Author(s):  
Gabriel Birkus ◽  
Michael J. M. Hitchcock ◽  
Tomas Cihlar
Keyword(s):  
Reverse Transcriptase ◽  
Hepg2 Cells ◽  
Mononuclear Cells ◽  
Lactate Production ◽  
Cell Types ◽  
Mitochondrial Toxicity ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Cellular Expression

ABSTRACT Drug-associated dysfunction of mitochondria is believed to play a role in the etiology of the various adverse symptoms that occur in human immunodeficiency virus (HIV)-infected patients treated with the nucleoside reverse transcriptase inhibitors (NRTIs). Tenofovir, a nucleotide analog recently approved for use in the treatment of HIV infection, was evaluated in vitro for its potential to cause mitochondrial toxicity and was compared to currently used NRTIs. Treatment with tenofovir (3 to 300 μM) for up to 3 weeks produced no significant changes in mitochondrial DNA (mtDNA) levels in human hepatoblastoma (HepG2) cells, skeletal muscle cells (SkMCs), or renal proximal tubule epithelial cells. The potencies of inhibition of mtDNA synthesis by the NRTIs tested were zalcitabine (ddC) > didanosine (ddI) > stavudine > zidovudine (ZDV) > lamivudine = abacavir = tenofovir, with comparable relative effects in the three cell types. Unlike ddC and ddI, tenofovir did not affect cellular expression of COX II and COX IV, two components of the mitochondrial cytochrome c oxidase complex. Lactate production was elevated by less than 20% in HepG2 cells or SkMCs following treatment with 300 μM tenofovir. In contrast, lactate synthesis increased by >200% in the presence of 300 μM ZDV. Thus, treatment of various human cell types with tenofovir at concentrations that greatly exceed those required for it both to have in vitro anti-HIV type 1 activity in peripheral blood mononuclear cells (50% effective concentration, 0.2 μM) and to achieve therapeutically relevant levels in plasma (maximum concentrations in plasma, 0.8 to 1.3 μM) is not associated with mitochondrial toxicity.

Nitroimidazoles Part 6. Synthesis, Structure and in Vitro anti-HIV Activity of New 5-substituted Piperazinyl-4-nitroimidazole Derivatives

2007 ◽  
Vol 18 (4) ◽  
pp. 191-200 ◽  
Author(s):  
Najim A Al-Masoudi ◽  
Yaseen A Al-Soud ◽  
Erik De Clercq ◽  
Christophe Pannecouque
Keyword(s):  
Reverse Transcriptase ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Phthalimide Derivative ◽  
Anti Hiv ◽  
Hiv 1

2-Amino-1-[4-(1-benzyl-2-ethyl-4-nitro-1 H-imidazol-5-yl)piperazin-1-yl]ethanone [6] was prepared from 1-(1-benzyl-2-ethyl-4-nitro-1 H-imidazol-5-yl) piperazine [3]. A series of new 2-oxoethyl-arylamide [9,10] and 2-oxoethyl-arylsulphonamide [11–14] derivatives were synthesized from [6] with the aim of developing new non-nucleoside reverse transcriptase inhibitors. Alternatively, the amine [17] was synthesized from [3] via the phthalimide derivative [16]. The arylsulphonamide derivatives [18–23] and the arylamide analogues [24–26] were synthesized from [17]. The compounds were evaluated for their anti-HIV-1 and anti-HIV-2 activity in MT-4 cells.

scholarly journals Mathematical Modelling of the Molecular Mechanisms of Interaction of Tenofovir with Emtricitabine against HIV

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1354
Author(s):  
Sara Iannuzzi ◽  
Max von Kleist
Keyword(s):  
Reverse Transcriptase ◽  
Reverse Transcription ◽  
Molecular Mechanisms ◽  
Synergistic Effects ◽  
Mechanistic Model ◽  
In Vitro Studies ◽  
Target Cells ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors

The combination of the two nucleoside reverse transcriptase inhibitors (NRTI) tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is used in most highly active antiretroviral therapies for treatment of HIV-1 infection, as well as in pre-exposure prophylaxis against HIV acquisition. Administered as prodrugs, these drugs are taken up by HIV-infected target cells, undergo intracellular phosphorylation and compete with natural deoxynucleoside triphosphates (dNTP) for incorporation into nascent viral DNA during reverse transcription. Once incorporated, they halt reverse transcription. In vitro studies have proposed that TDF and FTC act synergistically within an HIV-infected cell. However, it is unclear whether, and which, direct drug–drug interactions mediate the apparent synergy. The goal of this work was to refine a mechanistic model for the molecular mechanism of action (MMOA) of nucleoside analogues in order to analyse whether putative direct interactions may account for the in vitro observed synergistic effects. Our analysis suggests that depletion of dNTP pools can explain apparent synergy between TDF and FTC in HIV-infected cells at clinically relevant concentrations. Dead-end complex (DEC) formation does not seem to significantly contribute to the synergistic effect. However, in the presence of non-nucleoside reverse transcriptase inhibitors (NNRTIs), its role might be more relevant, as previously reported in experimental in vitro studies.

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