Understanding and Targeting the Endocannabinoid System with Activity‐Based Protein Profiling

Abstract

The endocannabinoid system (ECS) is a widespread modulatory system composed of cannabinoid receptors, endogenous signaling lipids termed endocannabinoids and the enzymes for the biosynthesis and degradation of these endocannabinoids. It plays a crucial role in diverse (patho)physiological functions, such as neurotransmission, neural development, synaptic plasticity, mood, food intake, and inflammation. Enzymes involved in the biosynthesis (e. g. NAPE‐PLD, DAGLs) and degradation (e. g. FAAH, MAGL) of endocannabinoids have attracted attention from both academia and industry due to their therapeutic potential. The discovery of selective inhibitors for these enzymes is important for functional assignment and biomedical applications. Activity‐based protein profiling (ABPP) has emerged as a powerful technique, which to a large extend accelerated the development of selective inhibitors for ECS enzymes. This review summarizes the representative activity‐based probes (ABPs) and small molecular inhibitors developed in the past two decades for ECS enzymes and will discuss the biological discoveries attributed by the application of these small molecules.

Activity‐Based Protein Profiling – Finding General Solutions to Specific Problems

“…This goal was best achieved with the fluorophosphonate (FP) reactive group, which, when coupled to biotin or fluorescent reporter tags, [12] proved useful for mapping several enzymes involved in endocannabinoid biosynthesis and degradation. [13][14][15][16][17][18][19] The breadth of coverage of FP probes concurrently opened up many additional opportunities for annotating poorly characterized members of the serine hydrolase family, which, when guided by modern human genetics, has facilitated an understanding of the mechanistic basis for rare neurological disorders caused by deleterious mutations in individual serine hydrolases. [20,21] Moreover, because FP probes react with active, but not inactive (e. g., zymogen precursor or endogenously inhibited) forms of serine hydrolases, [12,22,23] ABPP has provided a powerful way to report on the dynamic regulation of these enzymes in physiological and disease processes.…”