Variability in the activity of enzymes that metabolize drugs can cause person-to-person differences in the efficacy and safety of small molecule therapeutics. This has been studied in the context of several key enzymes involved in drug metabolism, however, the factors that influence carboxylesterase (CES) activity have been understudied despite the established role of CESs in the hydrolysis of many xenobiotic esters. We believe that this lack of knowledge is due to the scarcity and limitations of currently available techniques to investigate CES activity in live samples. To address the need for new approaches to study CESs, we have developed new fluorogenic chemical tools that can specifically report on CES activity in live cells. Subsequently, we demonstrate our tools can identify potential CES-mediated drug-drug interactions and use these tools to create an assay that can identify CES sequence-dependent activity variations in live cells. Overall, the chemical tools and approaches we generated can help uncover factors that result in variability in response to treatment with CES-substrate drugs.

Chemical biology approaches for uncovering interindividual variability in drug metabolism

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