The pharmacological landscape and therapeutic potential of serine hydrolases

Abstract

Serine hydrolases are one of the largest and most diverse enzyme classes in nature and have many crucial roles in human physiology and disease. Several serine hydrolases are targets of clinically approved drugs, but many enzymes in this family remain poorly characterized and lack selective inhibitors. Here, Bachovchin and Cravatt discuss the therapeutic potential of serine hydrolases and present novel inhibitor discovery strategies. Serine hydrolases perform crucial roles in many biological processes, and several of these enzymes are targets of approved drugs for indications such as type 2 diabetes, Alzheimer's disease and infectious diseases. Despite this, most of the human serine hydrolases (of which there are more than 200) remain poorly characterized with respect to their physiological substrates and functions, and the vast majority lack selective, in vivo-active inhibitors. Here, we review the current state of pharmacology for mammalian serine hydrolases, including marketed drugs, compounds that are under clinical investigation and selective inhibitors emerging from academic probe development efforts. We also highlight recent methodological advances that have accelerated the rate of inhibitor discovery and optimization for serine hydrolases, which we anticipate will aid in their biological characterization and, in some cases, therapeutic validation.