FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4377029078> ?p ?o ?g. }

• W4377029078 abstract "<b>Abstract ID 16698</b> <b>Poster Board 185</b> Nucleoside (Nuc) analogs are an essential class of antivirals. Nuc analogs are often structurally modified into a phosphoramidate prodrug form (ProTide) to boost their intracellular activation efficiency: generating more active metabolite triphosphate Nuc (TP-Nuc). To date, three ProTides have been approved by the FDA: tenofovir alafenamide (TAF), sofosbuvir (SBV), and remdesivir (RDV). After entering cells, TAF, SBV, and RDV are hydrolyzed by the intracellular esterases carboxylesterase 1 (CES1) and cathepsin A (CatA) to release their ester moieties. The abundance of CES1 and CatA in the cells determines the amount of TP-Nuc generated. In the human lung, CatA is the major ProTide activating enzyme. We hypothesize that a higher susceptivity to CatA could improve the activation of a ProTide in the lung. In this study, we evaluated the activation profiles of TAF, SBV, RDV in various cell lines on a molar equivalent dose basis (except for RDV in Huh-7 cells due to cytotoxicity). The cell lines tested were those commonly used in SARS-CoV-2 studies, including the human lung cell lines A549-ACE2-TMPRss2, Calu-3, and normal bronchial epithelial cells BEAS-2B; the colon cell line Caco-2; the liver cell lines Huh-7 and HepG2; and the African green monkey kidney epithelial cells Vero E6. After 6, 12, and 24 hours of drug incubation, the intracellular concentrations of the ProTides and their active metabolites were determined by LC-MS/MS. The expression profiles of activating enzymes (e.g., CES1 and CatA) and transporters (e.g., OATP1B1 and P-gp) were retrieved from available datasets. The contribution of CatA and CES1 to the activation of TAF, SBV, and RDV in BEAS-2B cells was further evaluated using CES1 and CatA inhibitors. The results showed that the three ProTides were activated in a cell-dependent manner. Overall, the ProTides achieved higher levels of TP-Nuc in the liver cell lines (i.e., Huh-7 and HepG2) than the other cell lines tested, which was associated with the higher expressions of OATP1B1 and CES1 in Huh-7 and HepG2 cells. In contrast, the three ProTides generated significantly less TP-Nuc in Vero E6 cells compared to the other cell lines, which was related to the abundant P-gp expression in Vero E6 cells. Among the human lung cell lines, the ProTide activation was comparable between the A549-ACE2-TMPRss2 and BEAS-2B cells and higher than the Calu-3 cells. Similar to the type II pneumocytes, the major SARS-CoV-2 infection target, the human lung cell lines exhibit a very low abundance of CES1 but a considerable expression of CatA. Moreover, our CES1 and CatA inhibition study confirmed the predominant role of CatA in activating ProTides in BEAS-2B cells. Interestingly, in all the human lung cell lines, TAF generated 2-3- and 6-10- folds higher amounts of TP-Nuc than RDV and SBV, respectively. This observation is highly correlated with the susceptivity of the three ProTides to CatA. Moreover, the TAF prodrug had a higher accumulation in the lung cell lines than RDV and SBV, indicating that cell permeability is another important factor for intracellular prodrug activation. In conclusion, TAF, SBV, and RDV bare considerable cell-dependent activation properties, which are associated with the expression patterns of activating enzymes and transporters across the different cell lines. Higher susceptivity to CatA and greater cell membrane permeability will enhance the activation of a ProTide in the human lung." @default.
• W4377029078 created "2023-05-19" @default.
• W4377029078 creator A5037659439 @default.
• W4377029078 creator A5055101832 @default.
• W4377029078 creator A5055659110 @default.
• W4377029078 creator A5071138367 @default.
• W4377029078 creator A5072918661 @default.
• W4377029078 date "2023-05-18" @default.
• W4377029078 modified "2023-09-29" @default.
• W4377029078 title "Understanding the cell-dependent activation of ProTides and its implications in optimizing the nucleoside antiviral prodrug design for treating pulmonary infections" @default.
• W4377029078 doi "https://doi.org/10.1124/jpet.122.166980" @default.
• W4377029078 hasPublicationYear "2023" @default.
• W4377029078 type Work @default.
• W4377029078 citedByCount "0" @default.
• W4377029078 crossrefType "proceedings-article" @default.
• W4377029078 hasAuthorship W4377029078A5037659439 @default.
• W4377029078 hasAuthorship W4377029078A5055101832 @default.
• W4377029078 hasAuthorship W4377029078A5055659110 @default.
• W4377029078 hasAuthorship W4377029078A5071138367 @default.
• W4377029078 hasAuthorship W4377029078A5072918661 @default.
• W4377029078 hasBestOaLocation W43770290781 @default.
• W4377029078 hasConcept C108215921 @default.
• W4377029078 hasConcept C109316439 @default.
• W4377029078 hasConcept C153911025 @default.
• W4377029078 hasConcept C159047783 @default.
• W4377029078 hasConcept C181199279 @default.
• W4377029078 hasConcept C185592680 @default.
• W4377029078 hasConcept C202751555 @default.
• W4377029078 hasConcept C2776543447 @default.
• W4377029078 hasConcept C2780880337 @default.
• W4377029078 hasConcept C54355233 @default.
• W4377029078 hasConcept C55493867 @default.
• W4377029078 hasConcept C79879829 @default.
• W4377029078 hasConcept C81885089 @default.
• W4377029078 hasConcept C86803240 @default.
• W4377029078 hasConceptScore W4377029078C108215921 @default.
• W4377029078 hasConceptScore W4377029078C109316439 @default.
• W4377029078 hasConceptScore W4377029078C153911025 @default.
• W4377029078 hasConceptScore W4377029078C159047783 @default.
• W4377029078 hasConceptScore W4377029078C181199279 @default.
• W4377029078 hasConceptScore W4377029078C185592680 @default.
• W4377029078 hasConceptScore W4377029078C202751555 @default.
• W4377029078 hasConceptScore W4377029078C2776543447 @default.
• W4377029078 hasConceptScore W4377029078C2780880337 @default.
• W4377029078 hasConceptScore W4377029078C54355233 @default.
• W4377029078 hasConceptScore W4377029078C55493867 @default.
• W4377029078 hasConceptScore W4377029078C79879829 @default.
• W4377029078 hasConceptScore W4377029078C81885089 @default.
• W4377029078 hasConceptScore W4377029078C86803240 @default.
• W4377029078 hasLocation W43770290781 @default.
• W4377029078 hasOpenAccess W4377029078 @default.
• W4377029078 hasPrimaryLocation W43770290781 @default.
• W4377029078 hasRelatedWork W1902207796 @default.
• W4377029078 hasRelatedWork W1966929003 @default.
• W4377029078 hasRelatedWork W1991783555 @default.
• W4377029078 hasRelatedWork W2023812702 @default.
• W4377029078 hasRelatedWork W2036003892 @default.
• W4377029078 hasRelatedWork W2039520479 @default.
• W4377029078 hasRelatedWork W2049539663 @default.
• W4377029078 hasRelatedWork W2068937921 @default.
• W4377029078 hasRelatedWork W2085771844 @default.
• W4377029078 hasRelatedWork W2107667230 @default.
• W4377029078 isParatext "false" @default.
• W4377029078 isRetracted "false" @default.
• W4377029078 workType "article" @default.