ArticlePloS one2018
Discovery of genetic variants of the kinases that activate tenofovir among individuals in the United States, Thailand, and South Africa: HPTN067.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers, 1 of them a synthesis that pooled it.
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Who cites it
8 citing papers in PubMed, 1 synthesis or guideline pooled it, 17 citations in OpenAlex.
- Prevalence of pyruvate kinase deficiency: A systematic literature review.European journal of haematology · 2020Pooled it
- Tenofovir Activation Is Diminished in the Brain and Liver of Creatine Kinase Brain-Type Knockout Mice.ACS pharmacology & translational science · 2024Article
- Tenofovir Activation is Diminished in the Brain and Liver of Creatine Kinase Brain-Type Knockout Mice.bioRxiv : the preprint server for biology · 2023Article
- Naturally Occurring Mutations to Muscle-Type Creatine Kinase Impact Its Canonical and Pharmacological Activities in a Substrate-Dependent Manner In Vitro.Molecular pharmacology · 2021Article
- Pharmacogenomics of Antiretroviral Drug Metabolism and Transport.Annual review of pharmacology and toxicology · 2021Review
- Elucidation of remdesivir cytotoxicity pathways through genome-wide CRISPR-Cas9 screening and transcriptomics.bioRxiv : the preprint server for biology · 2020Article
- Genetic variation of kinases and activation of nucleotide analog reverse transcriptase inhibitor tenofovir.Pharmacogenomics · 2019Review
- HIV Antiretroviral Pre-Exposure Prophylaxis: Development Challenges and Pipeline Promise.Clinical pharmacology and therapeutics · 2018Article
Corrections and comments
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Authors and funding
13 authors at 9 institutions in 4 countries.
Funding
Abstract
Tenofovir (TFV), a nucleotide reverse transcriptase inhibitor, requires two phosphorylation steps to form a competitive inhibitor of HIV reverse transcriptase. Adenylate kinase 2 (AK2) has been previously demonstrated to phosphorylate tenofovir to tenofovir-monophosphate, while creatine kinase, muscle (CKM), pyruvate kinase, muscle (PKM) and pyruvate kinase, liver and red blood cell (PKLR) each have been found to phosphorylate tenofovir-monophosphate to the pharmacologically active tenofovir-diphosphate. In the present study, genomic DNA isolated from dried blood spots collected from 505 participants from Bangkok, Thailand; Cape Town, South Africa; and New York City, USA were examined for variants in AK2, CKM, PKM, and PKLR using next-generation sequencing. The bioinformatics tools SIFT and PolyPhen predicted that 19 of the 505 individuals (3.7% frequency) carried variants in at least one kinase that would result in a decrease or loss of enzymatic activity. To functionally test these predictions, AK2 and AK2 variants were expressed in and purified from E. coli, followed by investigation of their activities towards tenofovir. Interestingly, we found that purified AK2 had the ability to phosphorylate tenofovir-monophosphate to tenofovir-diphosphate in addition to phosphorylating tenofovir to tenofovir-monophosphate. Further, four of the six AK2 variants predicted to result in a loss or decrease of enzyme function exhibited a ≥30% decrease in activity towards tenofovir in our in vitro assays. Of note, an AK2 K28R variant resulted in a 72% and 81% decrease in the formation of tenofovir-monophosphate and tenofovir-diphosphate, respectively. These data suggest that there are naturally occurring genetic variants that could potentially impact TFV activation.
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