Abstract
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.
Highlights
Nucleoside analogs denote a broad class of inhibitors that are successfully used in the treatment of cancers and many viral infections, such as Hepatitis B and C, Herpes viruses and HIV [1,2]
Like all other nucleoside analogs, nucleoside reverse transcriptase inhibitors (NRTI) are administered as prodrugs
We extend the model for the two types of direct interaction (DEC formation and effects on deoxynucleoside triphosphates (dNTP) pools) and assess for realistic parameter ranges if the proposed hypotheses can explain the observed levels of synergy between the drugs
Summary
Nucleoside analogs denote a broad class of inhibitors that are successfully used in the treatment of cancers and many viral infections, such as Hepatitis B and C, Herpes viruses and HIV [1,2]. Nucleoside analogs are investigated for treatment of. Most nucleoside analogs inhibit viral polymerase, which is necessary to maintain and multiply viral genomic information. Nucleoside analogs that target the RNA-dependent DNA polymerase of HIV are called nucleoside reverse transcriptase inhibitors (NRTIs) [6]. Like all other nucleoside analogs, NRTIs are administered as prodrugs. After uptake into HIV infected target cells [7], they undergo intracellular phosphorylation to form an analogue of (deoxy) nucleoside triphosphate [2]. The triphosphorylated NRTIs compete with the natural substrates for reverse transcriptase (RT) mediated incorporation into the nascent viral
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
