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Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir.

ABSTRACT: As antiretroviral therapy has become more accessible across the world and coformulations have improved patient compliance; the morbidity and mortality of HIV/AIDS has decreased. However, there is still a substantial gap in knowledge regarding the impact of genetic variation on the metabolism of and response to some of the most commonly prescribed antiretrovirals, including the nucleotide reverse transcriptase inhibitor tenofovir. While it has been scientifically established that tenofovir must be activated to be efficacious against HIV, the enzymes responsible for this activation have not been well characterized. The purpose of this review is to summarize and clarify the scientific knowledge regarding the enzymes that phosphorylate and activate this clinically important drug.

SUBMITTER: Hamlin AN

PROVIDER: S-EPMC6563221 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir.

Hamlin Allyson N AN Tillotson Joseph J Bumpus Namandjé N NN

Pharmacogenomics 20190110 2

As antiretroviral therapy has become more accessible across the world and coformulations have improved patient compliance; the morbidity and mortality of HIV/AIDS has decreased. However, there is still a substantial gap in knowledge regarding the impact of genetic variation on the metabolism of and response to some of the most commonly prescribed antiretrovirals, including the nucleotide reverse transcriptase inhibitor tenofovir. While it has been scientifically established that tenofovir must b ...[more]

PMID: 30628547

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Project description:Antiviral pre-exposure prophylaxis (PrEP) through daily drug administration can protect healthy individuals from HIV-1 infection. While PrEP was recently approved by the FDA, the potential long-term consequences of PrEP implementation remain entirely unclear. The aim of this study is to predict the efficacy of different prophylactic strategies with the pro-drug tenofovir-disoproxil-fumarate (TDF) and to assess the sensitivity towards timing- and mode of TDF administration (daily- vs. single dose), adherence and the number of transmitted viruses. We developed a pharmacokinetic model for TDF and its active anabolite tenofovir-diphosphate (TFV-DP) and validated it with data from 4 different trials, including 4 distinct dosing regimes. Pharmacokinetics were coupled to an HIV model and viral decay following TDF mono-therapy was predicted, consistent with available data. Subsequently, a stochastic approach was used to estimate the % infections prevented by (i) daily TDF-based PrEP, (ii) one week TDF started either shortly before, or -after viral exposure and (iii) a single dose oral TDF before viral challenge (sd-PrEP). Analytical solutions were derived to assess the relation between intracellular TFV-DP concentrations and prophylactic efficacy. The predicted efficacy of TDF was limited by a slow accumulation of active compound (TFV-DP) and variable TFV-DP half-life and decreased with increasing numbers of transmitted viruses. Once daily TDF-based PrEP yielded [Formula: see text]80% protection, if at least 40% of pills were taken. Sd-PrEP with 300 mg or 600 mg TDF could prevent [Formula: see text]50% infections, when given at least before virus exposure. The efficacy dropped to [Formula: see text]10%, when given 1 h before 24 h exposure. Efficacy could not be increased with increasing dosage or prolonged administration. Post-exposure prophylaxis poorly prevented infection. The use of drugs that accumulate more rapidly, or local application of tenofovir gel may overcome the need for drug administration long before virus exposure.

Project description:Background and purposeCardiovascular disease associated with antiretroviral therapy (ART) has become a major clinical challenge for HIV-positive patients. However, the role of ART in blood vessel growth is largely unknown. Here, we examined an integral component of ART, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and investigated their effects on key microvascular functions, including angiogenesis and lymphangiogenesis.Experimental approachThe angiogenesis/lymphangiogenesis capability of endothelial cells (ECs) was evaluated using migration, proliferation and tube formation assays in vitro, and mouse ear and Matrigel plug assays in vivo. Expressions of signalling molecules and mitochondrial antioxidant catalases were determined using Western blotting. Receptor tyrosine kinase (RTK) internalization and endocytosis were examined using flow cytometry and confocal immunofluorescence microscopy respectively. Mitochondrial DNA copy number and ROS were determined using quantitative real-time PCR and MitoSOX staining respectively.Key resultsPharmaceutical doses of NRTIs [azidothymidine (AZT), tenofovir disoproxil fumarate (TDF) and lamivudine (3TC)] inhibited angiogenesis and lymphangiogenesis both in vivo and in vitro by affecting the proliferation and migration of ECs. Correspondingly, NRTIs selectively attenuated the activation and transduction of endothelial RTK signals, VEGFR2 and FGFR1 pathways, in vascular ECs and the VEGFR3 pathway in lymphatic ECs. Both TDF and 3TC restrained RTKs' endocytosis into early endosomes but not internalization, while AZT blocked the protein maturation of RTKs. Excessive ROS levels were detected in NRTI-treated ECs, and the MnSOD mimic MnTMPyP alleviated the angiogenic/lymphangiogenic defects induced by NRTIs.Conclusions and implicationsNRTIs negatively regulate angiogenesis and lymphangiogenesis by inducing mitochondrial oxidative stress and subsequently impairing RTK signalling in ECs.Linked articlesThis article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

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Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir.

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Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir.

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