Human carboxylesterases (CESs) catalyze the hydrolysis of esters, amides, thioesters, carbonates, and carbamates. CES-mediated hydrolysis plays an important role in the metabolism of many drugs including the first FDA approved antiviral treatment for COVID-19 remdesivir (Veklury), the seizure control medication rufinamide (Banzel), and the flu antiviral drug oseltamivir (Tamiflu). CES activity is known to be influenced by a variety of factors including those that vary CES’s amino acid sequence such as single nucleotide polymorphisms (SNPs), alternative RNA splicing, and alternative translation start sites. This is best reported for one of the two predominant CESs, CES1, where some of these factors have been linked to adverse clinical outcomes when patients are treated with CES1-substrate therapeutics. Despite the importance of CES1 in drug metabolism, the factors that influence the activity of CES1 remain understudied compared to other enzymes involved in drug metabolism. To address the need to study CES1, we have developed a live cell fluorescence microscopy-based assay that can measure the activity of CES1 sequence variants. We expect the approach reported here will prove to be valuable in annotating the activity of CES1 sequence variants leading to discovery of additional sequences that could result in abnormally low metabolism of CES1-substrate drugs.

Chemical biology approach to annotate the influence of sequence variations on CES1 activity in live cells

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