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  • Review Article
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Carbonic anhydrases: novel therapeutic applications for inhibitors and activators

Nature Reviews Drug Discovery volume 7, pages 168–181 (2008)Cite this article

Key Points

  • Carbonic anhydrases (CAs) are widespread enzymes in bacteria, archaea and eukaryotes, and catalyze a crucially important physiological reaction: the hydration of carbon dioxide to bicarbonate and protons.

  • These enzymes are inhibited by several classes of compounds, such as sulphonamides, sulphamates and sulphamides, among others. The inhibitors bind to the catalytic zinc ion within the enzyme cavity.

  • Several such derivatives are clinically used inhibitors, such as acetazolamide, methazolamide, ethoxzolamide, dichlorophenamide, dorzolamide, brinzolamide, topiramate, zonisamide, sulpiride, sukthiame, celecoxib and valdecoxib among others. Several compounds are in clinical development, such as indisulam and COUMATE-667.

  • CA inhibitors (CAIs) are used in therapy as diuretic and antiglaucoma agents but also show anti-obesity and antitumour effects. Some compounds are in clinical development for such applications (obesity and cancer).

  • Most CAIs that are currently available show undesired side effects due to indiscriminate inhibition of CA isoforms other than the target one.

  • Many new CAIs are developed in the search of isozyme-selective compounds as potential drugs with fewer side effects.

  • Bacterial, fungal and protozoan CAs present in many pathogens have recently been considered as potential targets for the development of inhibitors with therapeutic applications.

  • CA activators (CAAs) participate in the enzyme catalytic cycle by facilitating the rate-determining step: a release of a proton from the zinc-coordinated water molecule to the reaction medium.

  • CAAs from various classes of compounds were developed in the past and characterized by means of X-ray crystallography and kinetic measurements. Such derivatives may lead to the development of anti-Alzheimer's disease agents and therapies to enhance memory.

Abstract

Carbonic anhydrases (CAs), a group of ubiquitously expressed metalloenzymes, are involved in numerous physiological and pathological processes, including gluconeogenesis, lipogenesis, ureagenesis, tumorigenicity and the growth and virulence of various pathogens. In addition to the established role of CA inhibitors (CAIs) as diuretics and antiglaucoma drugs, it has recently emerged that CAIs could have potential as novel anti-obesity, anticancer and anti-infective drugs. Furthermore, recent studies suggest that CA activation may provide a novel therapy for Alzheimer's disease. This article discusses the biological rationale for the novel uses of inhibitors or activators of CA activity in multiple diseases, and highlights progress in the development of specific modulators of the relevant CA isoforms, some of which are now being evaluated in clinical trials.

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Figure 1
Figure 2: Mechanisms of inhibition of carbonic anhydrase.
Figure 3: Fatty-acid biosynthesis and the role of carbonic anhydrase isozymes.
Figure 4: Mechanism of hypoxia-induced gene expression mediated by the HIF transcription factor.
Figure 5: Proteins and processes involved in pH regulation within the tumour cell.
Figure 6: A model for the role of urease and α- and β-CA in the maintenance of periplasmic pH in Helicobacter pylori.
Figure 7: A model of the regulation of filamentation and fungal capsule biosynthesis.

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Acknowledgements

Research from the author's laboratory was financed in part by two EU grants of the 6th framework programme (EUROXY and DeZnIt projects).

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  1. Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Rm 188, Via della Lastruccia 3, Sesto, I-50019, Fiorentino (Firenze), Italy

    Claudiu T. Supuran

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Competing interests

C.T.S. is an author on two patents that deal with carbonic anhydrase IX inhibitors: WO2004/048544 and WO2006/137092.

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High-ceiling (loop) diuretic

Diuretics are drugs that increase the rate of urine excretion. A high-ceiling (loop) diuretic inhibits the kidney's ability to reabsorb sodium in the ascending loop. This leads to an increased loss of sodium and water in the urine, as water normally follows sodium back into the extracellular fluid.

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Transport metabolons

Carbonic anhydrase isozymes that interact with anion exchanger proteins to form transport metabolons that regulate intracellular and/or extracellular pH.

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Supuran, C. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Discov 7, 168–181 (2008). https://doi.org/10.1038/nrd2467

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