Advances in the structural annotation of human carbonic anhydrases and impact on future drug discovery

ABSTRACT

Introduction: Of the 15 human carbonic anhydrase (CA, EC 4.2.1.1) isoforms known to date, for 11 the crystal structure is known. Many different classes of CA inhibitors (CAIs) were reported in the last decade, with a wealth of inhibition mechanisms, where apart from the classical one, the inhibitors do not bind to the zinc ion from the active site. The zinc binders (sulfonamides, dithiocarbamates and their isosteres, thiols, selenols, carboxylates, hydroxamates, carbamates) are not isoform-selective inhibitors, but the specificity of action may be achieved by decorating their scaffolds with tails that interact with amino acids at the entrance of the active site.

Areas covered: Herein, the authors review the advances in the structural annotation of human CAs. Furthermore, the authors look at the impact on drug discovery efforts as well as providing their expert perspectives.

Expert opinion: CAs are a unique example among metalloenzymes for which all regions of their spacious active sites may be used for inhibitor/activator binding, leading to a variety of inhibition mechanisms and profiles for the many chemotypes modulating their activity. This is exploited for the drug design of increasingly efficient and isoform-selective inhibitors, useful for many pharmacological applications.

KEYWORDS:

• Carbonic anhydrase
• inhibitor
• activator
• sulfonamide
• coumarin
• SLC-0111
• inhibition mechanism
• X-ray crystallography

Article highlights

• Carbonic anhydrases (CAs) catalyze the interconversion between CO₂ and bicarbonate with release of a proton and are involved in pH regulation and metabolism.

• At least 15 CA isoforms are present in humans, 12 of which are catalytically active and drug targets.

• CA inhibitors are used as diuretics, antiglaucoma, antiepileptic and antiobesity agents, and may have applications for the management of tumors, neuropathic pain and arthritis.

• The detailed annotation of the hCAs active site made possible the drug design of many inhibitors and activators that exploit all regions of the active site for binding, a situation unique to this enzyme.

• At least five different CA inhibition mechanisms are known: metal ion binders; compounds that anchor to the zinc-coordinated water; compounds that occlude the active site entrance; inhibitors which bind out of the active site, and compounds with unknown inhibition mechanism.

• Many inhibitors are in clinical use for decades, and SLC-0111, a sulfonamide CA IX/XII inhibitor is in Phase Ib/II clinical trials as an antitumor drug for the management of advanced, hypoxic solid tumors. CA activators show promise for the management of aging and as memory therapy.

• Hybrid drugs incorporating CA inhibitors and other pharmacological agents emerged as innovative tools to treat pathologies in which the CA activity is imbalanced.

This box summarizes key points contained in the article.

Declaration of interest

CT Supuran is the holder of many patents of CA inhibitors. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.