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Assessment of Mitochondrial Toxicity in Human Cells Treated with Tenofovir: Comparison with Other Nucleoside Reverse Transcriptase Inhibitors
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 and to achieve therapeutically relevant levels in plasma is not associated with mitochondrial toxicity. Expand
Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat
The clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition, establishing OAT2 as a likely relevantCreatinine transporter and further challenging the traditional view that Creatinine is solely transported by a cationic pathway. Expand
Crystal structures of HIV-1 reverse transcriptase with etravirine (TMC125) and rilpivirine (TMC278): implications for drug design.
Crystal structures were determined with wild-type and K103N HIV-1 reverse transcriptase with etravirine and rilpivirine, revealing a similar binding mode for TMC125 and TMC278, whether bound to wild- type or K103n RT. Expand
Cathepsin A Is the Major Hydrolase Catalyzing the Intracellular Hydrolysis of the Antiretroviral Nucleotide Phosphonoamidate Prodrugs GS-7340 and GS-9131
The main enzymatic activity responsible for the initial step in the intracellular activation of GS-7340 and GS-9131 was isolated from human peripheral blood mononuclear cells and identified as lysosomal carboxypeptidase A (CatA; EC 3.4.5). Expand
Tenofovir exhibits low cytotoxicity in various human cell types: comparison with other nucleoside reverse transcriptase inhibitors.
In conclusion, tenofovir exhibited weak cytotoxic effects in all cell types tested with less in vitro cytotoxicity than the majority of NRTIs currently used for the treatment of HIV disease. Expand
Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors
It is demonstrated that a wide range of viral and host PIs, with the exception of telaprevir and boceprevir, do not interfere with the antiretroviral activity of TAF. Expand
Activation of 9-[(R)-2-[[(S)-[[(S)-1-(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340) and Other Tenofovir Phosphonoamidate Prodrugs by Human Proteases
Results from the present study indicate that in addition to cathepsin A, a variety of serine and cysteine proteases cleave GS-7340 and other phosphonoamidate prodrugs of TFV should be considered peptidomimetic pro drugs ofTFV. Expand
Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148.
The ethylalaninyl phosphonamidate prodrug 5 (GS-9131) demonstrated favorable cathepsin A substrate properties, in addition to favorable in vitro intestinal and hepatic stabilities, leading to the nomination of 5 as a clinical candidate. Expand
Tenofovir diphosphate is a poor substrate and a weak inhibitor of rat DNA polymerases alpha, delta, and epsilon*.
Tenofovir diphosphate (PMPApp) is a weak inhibitor of DNA polymerases (pol) alpha, delta, and epsilon*, with values for the Ki for PMPApp ((PMPApp)Ki) relative to the Km for dATP ((dATP)Km) of 10.2,Expand
Metabolism and Antiretroviral Activity of Tenofovir Alafenamide in CD4+ T-Cells and Macrophages from Demographically Diverse Donors
These results indicate consistent intracellular metabolism and antiretroviral potency of TAF in relevant target cells of HIV-1 infection across multiple donors of variable gender, age and ethnicity, supporting further clinical investigation of T AF. Expand