The pharmacological landscape and therapeutic potential of serine hydrolases

The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA.
Nature Reviews Drug Discovery (Impact Factor: 41.91). 11/2011; 11(1):52-68. DOI: 10.1038/nrd3620
Source: PubMed


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.

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    • "In this respect, THC and AM3506 clearly differ from scopolamine, which disrupts performance of the mediating response (specifically decreasing the proportion of trials in which the rat responds only in the appropriate side hole during the delay; Panlilio et al. 2011). FAAH and MGL are members of the serine hydrolase family , which includes over 200 members, many of which are not well characterized (Bachovchin and Cravatt 2012). AM3506 is a sulfonylfluoride inhibitor and might show substantial differences in cross-reactivity with serine hydrolases compared to the more typical carbamate/urea inhibitors of FAAH like URB597 and PF-04457845. "
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    ABSTRACT: Rationale: Manipulations of the endocannabinoid system could potentially produce therapeutic effects with minimal risk of adverse cannabis-like side effects. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of the cannabinoid-receptor agonist, anandamide, and show promise for treating a wide range of disorders. However, their effects on learning and memory have not been fully characterized. Objectives: We determined the effects of five structurally different FAAH inhibitors in an animal model of working memory known to be sensitive to impairment by delta-9 tetrahydrocannabinol (THC). Methods: A delayed nonmatching-to-position procedure was used in rats. Illuminated nosepoke holes were used to provide sample cues (left versus right) and record responses (correct versus incorrect) after delays ranging from 0 to 28 s. Various test drugs were given acutely up to two times per week before daily sessions. Results: One FAAH inhibitor, AM3506 (3 mg/kg), decreased accuracy in the memory task. Four other FAAH inhibitors (URB597, URB694, PF-04457845, and ARN14633) and a monoacylglycerol lipase inhibitor (JZL184, which blocks the degradation of the endocannabinoid 2-arachidonoylglycerol) had no effect. Testing of AM3506 in combination with antagonists for receptors known to be affected by anandamide and other fatty acid amides indicated that the impairment induced by AM3506 was mediated by cannabinoid CB1 receptors, and not by alpha-type peroxisome proliferator-activated receptors (PPAR-alpha) or vanilloid transient receptor potential cation channels (TRPV1). Conclusions: FAAH inhibitors differ with respect to their potential for memory impairment, abuse liability, and probably other cannabis-like effects, and they should be evaluated individually for specific therapeutic and adverse effects.
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    • "Irreversible inhibitors are largely electrophilic compounds that covalently modify the conserved catalytic serine nucleophile of SHs. Activated carbamates, for instance, irreversibly carbamylate the catalytic serine of SHs, and, in select cases, have been advanced to furnish selective and in vivo-active inhibitors and drugs for individual SHs (Bachovchin and Cravatt, 2012). Carbamate inhibitors can be operationally deconstructed into two primary elements: the staying group (SG), which remains covalently bound to the SH catalytic serine, and the leaving group (LG), which is displaced by the enzyme's serine nucleophile. "
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    ABSTRACT: Serine hydrolase inhibitors, which facilitate enzyme function assignment and are used to treat a range of human disorders, often act by an irreversible mechanism that involves covalent modification of the serine hydrolase catalytic nucleophile. The portion of mammalian serine hydrolases for which selective inhibitors have been developed, however, remains small. Here, we show that N-hydroxyhydantoin (NHH) carbamates are a versatile class of irreversible serine hydrolase inhibitors that can be modified on both the staying (carbamylating) and leaving (NHH) groups to optimize potency and selectivity. Synthesis of a small library of NHH carbamates and screening by competitive activity-based protein profiling furnished selective, in vivo-active inhibitors and tailored activity-based probes for multiple mammalian serine hydrolases, including palmitoyl protein thioesterase 1, mutations of which cause the human disease infantile neuronal ceroid lipofuscinosis. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "To better exploit Momordica cyclic peptides for biomedical applications, it is imperative that their evolvability, i.e. the ability to acquire new function through structural changes (Tokuriki and Tawfik 2009), be understood. Given the function of Momordica cyclic peptides as potent trypsin inhibitors, knowledge of their evolvability is particularly useful for developing novel inhibitors of other evolutionarily related serine proteases – many of which play crucial roles in pathophysiological processes, such as inflammation and blood clotting (Bachovchin and Cravatt 2012). "
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    ABSTRACT: Cyclic proteins have evolved for millions of years across all kingdoms of life to confer structural stability over their acyclic counterparts while maintaining intrinsic functional properties. Here, we show that cyclic miniproteins (or peptides) from Momordica (Cucurbitaceae) seeds evolved in species that diverged from an African ancestor around 19 Ma. The ability to achieve head-to-tail cyclization of Momordica cyclic peptides appears to have been acquired through a series of mutations in their acyclic precursor coding sequences following recent and independent gene expansion event(s). Evolutionary analysis of Momordica cyclic peptides reveals sites that are under selection, highlighting residues that are presumably constrained for maintaining their function as potent trypsin inhibitors. Molecular dynamics of Momordica cyclic peptides in complex with trypsin reveals site-specific residues involved in target binding. In a broader context, this study provides a basis for selecting Momordica species to further investigate the biosynthesis of the cyclic peptides and for constructing libraries that may be screened against evolutionarily related serine proteases implicated in human diseases.
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