Mammalian carboxylesterases: from drug targets to protein therapeutics.
Our understanding of the detailed recognition and processing of clinically useful therapeutic agents has grown rapidly in recent years, and we are now able to begin to apply this knowledge to the rational treatment of disease. Mammalian carboxylesterases (CEs) are enzymes with broad substrate specificities that have key roles in the metabolism of a wide variety of clinical drugs, illicit narcotics and chemical nerve agents. Here, the functions, mechanism of action and structures of human CEs are reviewed, with the goal of understanding how these proteins are able to act in such a non-specific fashion, yet catalyze a remarkably specific chemical reaction. Current approaches to harness these enzymes as protein-based therapeutics for drug and chemical toxin clearance are described, as well as their uses for targeted chemotherapeutic prodrug activation. Also included is an outline of how selective CE inhibitors could be used as co-drugs to improve the efficacy of clinically approved agents.
Redinbo
Matthew R
MR
Department of Chemistry, Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599-3290, USA. redinbo@unc.edu
Potter
Philip M
PM
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D011506:Proteins; D002265:Carboxylic Ester Hydrolases