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The pharmacological landscape and therapeutic potential of serine hydrolases

Nature Reviews Drug Discovery volume 11, pages 52–68 (2012)Cite this article

Subjects

Key Points

  • Serine hydrolases are one of the largest and most diverse classes of enzymes found in eukaryotes and prokaryotes, including ∼240 members in humans.

  • Several clinically approved drugs target serine hydrolases. Prominent among these therapeutics are inhibitors of thrombin, acetylcholinesterase and dipeptidyl peptidase 4 that are used to treat clotting disorders, Alzheimer's disease-associated dementia and diabetes, respectively.

  • Many serine hydrolases have recently emerged as enzymes with therapeutic potential and are the focus of intense inhibitor discovery efforts.

  • Compounds that act through covalent mechanisms have proved to be especially effective at selectively inhibiting serine hydrolases. Here, we highlight the mechanism-based electrophiles that have successfully formed the basis of selective, in vivo-active inhibitors (including several approved drugs) and also review promising new chemotypes that have recently been discovered.

  • Activity-based protein profiling has facilitated the discovery of dysregulated serine hydrolases in disease and has enabled the rapid development of selective inhibitors for the functional characterization of these enzymes.

Abstract

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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Figure 1: Schematic representation of the serine hydrolase catalytic cycle.
Figure 2: The human serine hydrolases.
Figure 3: Activity-based protein profiling for enzyme and inhibitor discovery.
Figure 4: Fluorescence polarization-ABPP platform for high-throughput screening.

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Acknowledgements

We thank the Cravatt laboratory for helpful discussions. This work was supported by grants from the US National Institutes of Health (DA025285, GM090294, CA132630, DA017259, DA009789 and CA087660), the National Science Foundation (predoctoral fellowship to D.A.B.), the California Breast Cancer Research Program (predoctoral fellowship to D.A.B.), and The Skaggs Institute for Chemical Biology.

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  1. The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, 92037, California, USA

    Daniel A. Bachovchin & Benjamin F. Cravatt

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  1. Daniel A. Bachovchin
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  2. Benjamin F. Cravatt
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Correspondence to Benjamin F. Cravatt.

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Competing interests

Benjamin F. Cravatt is a co-founder and advisor for a biotechnology company interested in developing inhibitors for serine hydrolase as therapeutic targets.

Supplementary information

Supplementary information S1 (table)

Drugs that target viral and bacterial serine hydrolases. (PDF 283 kb)

Supplementary information S2 (table)

The human serine hydrolases. (PDF 188 kb)

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Glossary

Warheads

Reactive chemical groups that covalently bind to specific amino acid residues of the target enzyme.

Zymogens

Inactive enzyme precursors, or pro-enzymes, that require a biochemical event (for example, a hydrolysis reaction) to convert them into active enzymes.

Thrombi

Aggregations of platelets, fibrin and cells.

Coagulation cascade

A stepwise process involving the sequential activation of several serine protease zymogens by limited proteolysis that results in the formation of fibrin blood clots.

Prodrug

A pharmacological entity administered in a largely inactive form that is metabolized in vivo into an active drug.

Cachexia

A wasting syndrome characterized by the uncontrolled loss of muscle and adipose tissue.

Fluorescence polarization

A measure of the apparent size of a fluorophore; it is widely used to study molecular interactions. Briefly, a fluorophore excited with plane-polarized light will emit polarized light parallel to the plane of excitation unless it rotates in the excited state. As the speed of rotational diffusion is inversely proportional to molecular volume, the resulting extent of depolarization gives a relative estimate of the size of the fluorophore.

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Bachovchin, D., Cravatt, B. The pharmacological landscape and therapeutic potential of serine hydrolases. Nat Rev Drug Discov 11, 52–68 (2012). https://doi.org/10.1038/nrd3620

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