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Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter

Nature Reviews Drug Discovery volume 14, pages 329–345 (2015)Cite this article

Subjects

Key Points

  • Hydrogen sulfide (H2S) is an important signalling molecule; it influences physiological and pathophysiological processes throughout the body.

  • Accurate measurement of hydrogen sulfide remains a challenge, largely because it is highly reactive. H2S synthesis from the microbiome contributes substantially to 'tissue levels' of H2S.

  • In circumstances of anoxia or hypoxia, H2S can 'rescue' mitochondria. H2S also exerts important anti-inflammatory and cytoprotective effects while driving the resolution of tissue injury.

  • Animal studies of several H2S-releasing drugs show considerable promise for the safe treatment of a wide range of disorders, and several such drugs are now in clinical trials.

  • Coupling of an H2S-releasing moiety to other drugs, such as anti-inflammatory drugs, can improve efficacy and/or substantially reduce toxicity.

  • Based on studies in animal models, H2S-based drugs may be effective in chemoprevention of cancer, and have also shown promise in the treatment of several neurological disorders, such as Alzheimer disease.

Abstract

Hydrogen sulfide (H2S) has become recognized as an important signalling molecule throughout the body, contributing to many physiological and pathological processes. In recent years, improved methods for measuring H2S levels and the availability of a wider range of H2S donors and more selective inhibitors of H2S synthesis have helped to more accurately identify the many biological effects of this highly reactive gaseous mediator. Animal studies of several H2S-releasing drugs have demonstrated considerable promise for the safe treatment of a wide range of disorders. Several such drugs are now in clinical trials.

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Figure 1: Cytosolic and mitochondrial production and functions of H2S.
Figure 2: The pathogenic roles of H2S at different stages of diabetes development.
Figure 3: Anti-inflammatory and cytoprotective targets of H2S.

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Acknowledgements

J.L.W. and R.W. are supported by grants from the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. Department of Physiology & Pharmacology, University of Calgary, Calgary, Alberta, T2N 4N1, Canada

    John L. Wallace

  2. Department of Pharmacology & Toxicology, University of Toronto, Toronto, M5S 2J7, Ontario, Canada

    John L. Wallace

  3. Department of Biology, Lakehead University, Thunder Bay, P7B5E1, Ontario, Canada

    Rui Wang

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J.L.W. is a founder and director of Antibe Therapeutics Inc. R.W. declares no competing interests.

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Glossary

Cystathionine γ-lyase

(CSE). An enzyme that converts L-cysteine into hydrogen sulfide, pyruvate and ammonia. It requires the cofactor pyridoxal phosphate (vitamin B6) for this activity.

Cystathionine β-synthase

(CBS). An enzyme that catalyses the conversion of homocysteine to cystathionine (the first step in the trans-sulfuration pathway) and the condensation of homocysteine and cysteine to form cystathionine and hydrogen sulfide.

Cysteine aminotransferase

(CAT). An enzyme that catalyses the conversion of L-cysteine and α-ketoglutarate to 3-mercaptopyruvate and glutamate. Another enzyme, 3-mercaptosulfurtransferase, can then catabolize the generation of hydrogen sulfide from 3-mercaptopyruvate.

4-aminopyridine

(4-AP). One of three isomeric amines of pyridine, which is widely used as a research tool to characterize the subtypes of potassium channels.

Calcium sparks

Intracellular Ca2+ release events that play an important role in excitation–contraction coupling.

Tag-switch method

A technique used to measure protein S-sulfhydration, whereby S-sulfhydrated residues are labelled to form thioether conjugates.

Two-kidney-one-clip model

A model of hypertension induced by chronically constricting one renal artery while the other renal artery remains fully perfused.

Hyperhomocysteinaemia

A condition characterized by abnormally high levels of homocysteine in the blood. The major causes of this condition are deficiencies of vitamins B6, B9 and B12, and mutations in the gene encoding the enzyme 5-methyltetrahydrofolate.

Streptozotocin

A chemical commonly used to induce diabetes in laboratory animals, as it is toxic to the insulin-producing β-cells in the pancreas.

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Wallace, J., Wang, R. Hydrogen sulfide-based therapeutics: exploiting a unique but ubiquitous gasotransmitter. Nat Rev Drug Discov 14, 329–345 (2015). https://doi.org/10.1038/nrd4433

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