REverSe TRanscrIptase chain termination (RESTRICT) for selective measurement of nucleotide analogs used in HIV care and prevention

Sufficient drug concentrations are required for efficacy of antiretroviral drugs used in HIV care and prevention. Measurement of nucleotide analogs, included in most HIV medication regimens, enables monitoring of short‐ and long‐term adherence and the risk of treatment failure. The REverSe TRanscrIp...

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Bibliographic Details
Published in:	Bioengineering & translational medicine Vol. 8; no. 1; pp. e10369 - n/a
Main Authors:	Olanrewaju, Ayokunle O., Sullivan, Benjamin P., Gim, Alicia H., Craig, Cosette A., Sevenler, Derin, Bender, Andrew T., Drain, Paul K., Posner, Jonathan D.
Format:	Journal Article
Language:	English
Published:	Hoboken, USA John Wiley & Sons, Inc 01-01-2023 Wiley
Subjects:	Acids adherence monitoring Analogs Antiretroviral drugs Behavioral sciences Biomarkers Chains Drug dosages Dyes enzymatic assay Enzymes HIV Human immunodeficiency virus Immunoassay Monitoring nucleotide analog nucleotide reverse transcriptase inhibitor Nucleotides Probabilistic models reverse transcriptase inhibitor tenofovir diphosphate therapeutic drug monitoring Zidovudine reverse transcriptase inhibitor nucleotide reverse transcriptase inhibitor enzymatic assay nucleotide analog adherence monitoring tenofovir diphosphate therapeutic drug monitoring
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Summary:	Sufficient drug concentrations are required for efficacy of antiretroviral drugs used in HIV care and prevention. Measurement of nucleotide analogs, included in most HIV medication regimens, enables monitoring of short‐ and long‐term adherence and the risk of treatment failure. The REverSe TRanscrIptase Chain Termination (RESTRICT) assay rapidly infers the concentration of intracellular nucleotide analogs based on the inhibition of DNA synthesis by HIV reverse transcriptase enzyme. Here, we introduce a probabilistic model for RESTRICT and demonstrate selective measurement of multiple nucleotide analogs using DNA templates designed according to the chemical structure of each drug. We measure clinically relevant concentrations of tenofovir diphosphate, emtricitabine triphosphate, lamivudine triphosphate, and azidothymidine triphosphate with agreement between experiment and theory. RESTRICT represents a new class of activity‐based assays for therapeutic drug monitoring in HIV care and could be extended to other diseases treated with nucleotide analogs.
Bibliography:	Funding information Center for AIDS Research, University of Washington; M.J. Murdock Charitable Trust; Momental Foundation; National Institute of Allergy and Infectious Diseases, Grant/Award Numbers: R01AI136648, R01AI157756, R21AI127200; University of Washington/Fred Hutch Center for AIDS Research; M. J. Murdock Charitable Trust; National Institute of Biomedical Imaging and Bioengineering, Grant/Award Number: U54EB027690; University of Washington CoMotion Innovation Gap Fund; National Institutes of Health, Grant/Award Number: AI027757 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Funding information Center for AIDS Research, University of Washington; M.J. Murdock Charitable Trust; Momental Foundation; National Institute of Allergy and Infectious Diseases, Grant/Award Numbers: R01AI136648, R01AI157756, R21AI127200; University of Washington/Fred Hutch Center for AIDS Research; M. J. Murdock Charitable Trust; National Institute of Biomedical Imaging and Bioengineering, Grant/Award Number: U54EB027690; University of Washington CoMotion Innovation Gap Fund; National Institutes of Health, Grant/Award Number: AI027757
ISSN:	2380-6761 2380-6761
DOI:	10.1002/btm2.10369