Birkus_2015_Antimicrob.Agents.Chemother_60_316

Reference

Title : Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors - Birkus_2015_Antimicrob.Agents.Chemother_60_316
Author(s) : Birkus G , Bam RA , Willkom M , Frey CR , Tsai L , Stray KM , Yant SR , Cihlar T
Ref : Antimicrobial Agents & Chemotherapy , 60 :316 , 2015
Abstract :

Tenofovir alafenamide fumarate (TAF) is an oral phosphonoamidate prodrug of the HIV reverse transcriptase nucleotide inhibitor tenofovir (TFV). Previous studies suggested a principal role for the lysosomal serine protease cathepsin A (CatA) in the intracellular activation of TAF. Here we further investigated the role of CatA and other human hydrolases in the metabolism of TAF. Overexpression of CatA or liver carboxylesterase 1 (Ces1) in HEK293T cells increased intracellular TAF hydrolysis 2- and 5-fold, respectively. Knockdown of CatA expression with RNA interference (RNAi) in HeLa cells reduced intracellular TAF metabolism 5-fold. Additionally, the anti-HIV activity and the rate of CatA hydrolysis showed good correlation within a large set of TFV phosphonoamidate prodrugs. The covalent hepatitis C virus (HCV) protease inhibitors (PIs) telaprevir and boceprevir potently inhibited CatA-mediated TAF activation (50% inhibitory concentration [IC50] = 0.27 and 0.16 muM, respectively) in vitro and also reduced its anti-HIV activity in primary human CD4(+) T lymphocytes (21- and 3-fold, respectively) at pharmacologically relevant concentrations. In contrast, there was no inhibition of CatA or any significant effect on anti-HIV activity of TAF observed with cobicistat, noncovalent HIV and HCV PIs, or various prescribed inhibitors of host serine proteases. Collectively, these studies confirm that CatA plays a pivotal role in the intracellular metabolism of TAF, whereas the liver esterase Ces1 likely contributes to the hepatic activation of TAF. Moreover, this work demonstrates 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.

PubMedSearch : Birkus_2015_Antimicrob.Agents.Chemother_60_316
PubMedID: 26503655
Gene_locus related to this paper: human-CES1

Related information

Citations formats

Birkus G, Bam RA, Willkom M, Frey CR, Tsai L, Stray KM, Yant SR, Cihlar T (2015)
Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors
Antimicrobial Agents & Chemotherapy 60 :316

Birkus G, Bam RA, Willkom M, Frey CR, Tsai L, Stray KM, Yant SR, Cihlar T (2015)
Antimicrobial Agents & Chemotherapy 60 :316