Multi- and polypharmacology of carbonic anhydrase inhibitors
Abstract
Eight genetically distinct families of the enzyme carbonic anhydrase (CA, EC 4.2.1.1) have been described in organisms overall in the phylogenetic tree. They catalyze the hydration of CO2 to bicarbonate and protons and are involved in pH regulation, chemosensing, and metabolism. The 15 α-CA isoforms present in humans are pharmacological drug targets known for decades, their inhibitors being used as diuretics, antiglaucoma, antiepileptic, or antiobesity drugs, as well as for the management of acute mountain sickness, idiopathic intracranial hypertension, and recently, as antitumor theragnostic agents. Other potential applications include the use of CA inhibitors (CAIs) in inflammatory conditions, cerebral ischemia, neuropathic pain, or Alzheimer/Parkinson disease management. CAs from pathogenic bacteria, fungi, protozoans, and nematodes have started to be considered as drug targets in recent years, with notable advances being registered. CAIs have a complex multipharmacology probably unique to this enzyme, which has been exploited intensely but may lead to other relevant applications in the future due to the emergence of drug design approaches that afforded highly isoform-selective compounds for most α-CAs known to date. They belong to a multitude of chemical classes (sulfonamides and isosteres, [iso]coumarins and related compounds, mono- and dithiocarbamates, selenols, ninhydrines, boronic acids, benzoxaboroles, etc). The polypharmacology of CAIs will also be discussed…
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