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

Israel Journal of Chemistry, vol. 63

Abstract

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.

Authors 3

1. Na Zhu Aachen Department of Molecular Physiology

   Leiden University · Oncode Institute

   Affiliation as printed

   Department of Molecular Physiology Leiden Institute of Chemistry Leiden University & Oncode Institute 2333 CC Leiden the Netherlands

   Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University & Oncode Institute, 2333 CC Leiden, the Netherlands

2. Antonius P. A. Janssen Aachen Department of Molecular Physiology

   Leiden University · Oncode Institute

   Affiliation as printed

   Department of Molecular Physiology Leiden Institute of Chemistry Leiden University & Oncode Institute 2333 CC Leiden the Netherlands

   Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University & Oncode Institute, 2333 CC Leiden, the Netherlands

3. Mario van der Stelt corresponding Aachen Department of Molecular Physiology

   Leiden University · Oncode Institute

   Affiliation as printed

   Department of Molecular Physiology Leiden Institute of Chemistry Leiden University & Oncode Institute 2333 CC Leiden the Netherlands

   Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University & Oncode Institute, 2333 CC Leiden, the Netherlands