Revealing human carboxylesterase 1 (CES1) sequence‐dependent activity variations using fluorescent chemical tools

Abstract

Carboxylesterases (CESs) play a key role in the metabolism of many small molecule therapeutics including Remdesivir, the first drug authorized by the FDA to treat COVID‐19. The overall activity of CESs, however, can be drastically different person to person. This interindividual variability has been shown to influence the metabolism and, in some cases, clinical outcomes of patients treated with drugs that are substrates for carboxylesterase 1 (CES1). The factors that contribute to this interindividual variability have not been fully uncovered, despite the established importance of CES1 in drug metabolism. We believe that this lack of knowledge is due to the scarcity and limitations of currently available approaches to study CES1 activity in live samples. To address these challenges, we have developed new fluorescent chemical tools that can specifically report on CES1 activity in live cells. Subsequently, we deployed our CES1 fluorescent chemical tools in a new chemical biology approach to monitor CES1 sequence‐dependent activity variations in live cells. Overall, the tools and approaches we develop can help uncover factors that result in interindividual variability of CES1 activity.