Carbonic anhydrase inhibitors and activators and their use in therapy

Among the 16 different alpha-carbonic anhydrase (CA, EC 4.2.1.1) isoforms isolated in mammals, 13 possess catalytic activity for the reversible hydration of carbon dioxide to bicarbonate. Some of them are cytosolic (CA 1, CA 11, CA 111, CA VII, CA XIII), others are membrane-bound (CA IV, CA IX, CA XII, CA XIV and CA XV); CA VA and CA VB are mitochondrial and CA VI is secreted in saliva and milk. Representatives of the beta - delta-CA family are highly abundant in fungi, yeasts, plants, diatoms, bacteria and archaea. These enzymes are very efficient catalysts playing crucial physiological/pathological roles related to acid-base homeostasis, secretion of electrolytes, transport of ions, biosynthetic reactions and tumourigenesis. Many of the catalytically active CAs present in humans are targets for the drug design. CA inhibitors of the sulfonamide, sulfamate or sulfamide type show applications as antiglaucoma, antiepileptic, antiobesity or antitumour agents and they target different isoforms involved in such processes (CA 11 and XII for the antiglaucoma action; CA VII and 11 for the antiepileptic one; CA VA and VB for the antiobesity activity and CA IX and XII for the antitumour effects, respectively). Various CAs present in pathogenic organisms (such as Plasmodium falciparum, Helicobacter pylori, Mycobacterium tuberculcsis, Candida albicans, Cryptococcus neoformans etc.) also started to be investigated recently as drug targets. Activation of mammalian CAs by various classes of activators intensively studied may ultimately lead to the design of pharmacologically useful derivatives for the enhancement of synaptic efficacy, which may represent a conceptually new approach for the treatment of depression, Alzheimer's disease, ageing and other conditions in which spatial learning and memory therapy must be enhanced. Important progress has been achieved in the drug design of CA inhibitors and activators both by synthesising novel classes of such agents, in the search of compounds with selectivity for various isozymes and also by resolving the X-ray crystal structure of adducts of different CA isoforms with inhibitors/activators with pharmacological applications.