Few molecules in human cells contain esters. Likewise, human cells have high esterase activity. That activity is exploited routinely for the delivery of pharmacological agents as prodrugs in which carboxyl moieties are masked as esters. The esters in prodrugs are typically made with ethanol, which is not toxic as a byproduct of ester hydrolysis. Although esterases vary in different tissues and cell types, variations in esterase specificity are not exploited in the current pharmacopeia. The proposed research seeks to provide the technological basis for tailoring the alcohol portion of prodrugs (and latent probes) to particular physiological contexts. Work will begin by developing a high-throughput assay for the esterase-catalyzed hydrolysis of alkyl esters in which the alcohol protein of the ester is a variable. Then, a library of esters will be synthesized by reacting alcohols with a common intermediate. Finally, a profile of esterase substrate specificity will be developed across a wide range of tissues, cell types, and sera. The ensuing profile of the substrate specificity of esterases endogenous in contexts most relevant for both drug development and basic research in chemical biology will enable future efforts to take prodrug and latent probe design into a new realm.

Public Health Relevance

Today, approximately 20% of drugs are administered to patients as prodrugs? inactive forms that are converted by enzymes within human cells into active forms. The goal of this project is to enable the design of prodrugs that are activated preferentially in targeted cells and tissues. The ensuing prodrugs are expected to be more effective than current prodrugs and to incur fewer side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21GM135780-01
Application #
9874623
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fabian, Miles
Project Start
2019-09-20
Project End
2021-08-31
Budget Start
2019-09-20
Budget End
2020-08-31
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02142