Research

Genetic polymorphisms are a major contributing factor to the interindividual variability in the expression and activity of drug-metabolizing enzymes (DMEs) and transporters. The Zhu laboratory is interested in determining genetic variants associated with interindividual variability of DMEs and transporters using both basic and clinical approaches. Professor Zhu and his colleagues are among the first to demonstrate that genetic variants of carboxylesterase 1 (CES1), the primary hepatic hydrolase in humans, can markedly impair the function of CES1 and significantly alter the pharmacokinetics and pharmacodynamics of drugs metabolized by the enzyme. He has extended his pharmacogenetic research beyond CES1 to many other clinically important enzymes and transporters. The long-term goal of this line of research is to identify genetic variants that can serve as biomarkers to predict individual responses to specific medications and to apply this information to optimize pharmacotherapy. 

Pharmacogenetics of drug-metabolizing enzymes (DMEs) has been increasingly utilized in clinical practice to individualize drug therapy and has shown great potential for improving pharmacotherapy outcomes. However, it has been well recognized that genetic variants can only explain a portion, sometimes only a small fraction, of interindividual variability in the expression and activity of DMEs and the associated variability in drug responses. The inability of pharmacogenetics to predict DME function is partially due to that DME protein expression could be regulated by non-genetic factors. Therefore, protein biomarkers capable of predicting DME expression levels have the potential to be used as a complementary tool to pharmacogenomics to individualize pharmacotherapy. Our laboratory established several novel LC-MS/MS-based proteomics methods and bioinformatic tools to identify and quantify proteins in complex biological samples (e.g., plasma and tissues). We are particularly interested in plasma protein biomarkers for the prediction of hepatic DME protein expression levels since the liver is the primary organ responsible for drug metabolism. 

Prodrugs are activated by specific DMEs in vivo to form their active metabolites. The activation step is essential for prodrugs to exert their intended therapeutic effects. The expression levels of prodrug-activating enzymes vary markedly between tissues, which results in various levels of active metabolites among different organs. Increasing the selectivity of prodrug activation in its target tissue (e.g., anti-COVID-19 prodrug activation in the lung) could enhance the efficacy and safety of the prodrug. We have profiled the protein expression patterns of prodrug-activating enzymes in various organs. We have also revealed that modifying the prodrug structure could alter its specificity to different activating enzymes. One of our research objectives in this area is to utilize a prodrug-activating enzyme proteomics-based strategy to develop novel nucleotide prodrugs for treating COVID-19 and other viral infections in the lung. These prodrugs could be more efficiently activated in the lung and exhibit greater bioavailability than existing anti-SARS-CoV-2 prodrugs, such as remdesivir.