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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    • "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.
    Chemistry & biology 06/2015; 22(7). DOI:10.1016/j.chembiol.2015.05.018 · 6.65 Impact Factor
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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.
    Molecular Biology and Evolution 11/2014; 32(2). DOI:10.1093/molbev/msu307 · 9.11 Impact Factor
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    • "The second involves the preliminary immobilization of the inhibitor on the support and a subsequent solid/liquid inhibition-capture process [7]. Within the hydrolytic enzyme family, serine and cysteine hydrolases , including proteases, lipases and carboxylesterases, are the most abundant classes of enzymes in the living world [8]. In particular, lipases represent a specific class of carboxylesterases hydrolyzing insoluble triacylglycerol substrates and play key roles in fat metabolism, energy mobilization, and bacterial growth. "
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    ABSTRACT: A synthetic phosphonate inhibitor designed for lipase inhibition but displaying a broader range of activity was covalently immobilized on a solid support to generate a function-directed tool targeting serine hydrolases. To achieve this goal, straightforward and reliable analytical techniques were developed, allowing the monitoring of the solid support's chemical functionalization, enzyme capture processes and physisorption artifacts. This grafted inhibitor was tested on pure lipases and serine proteases from various origins, and assayed for the selective capture of lipases from several complex biological extracts. The direct identification of captured enzymes by mass spectrometry brought the proof of concept on the efficiency of this supported covalent inhibitor. The features and limitations of this "enzyme-fishing" proteomic tool provide new insight on solid-liquid inhibition process.
    Biochimie 07/2014; 107:124-134. DOI:10.1016/j.biochi.2014.07.015 · 2.96 Impact Factor
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