Modulation of carbonic anhydrase activity and its applications in therapy

By catalysing a very simple physiological reaction, the hydration of carbon dioxide (CO2) to bicarbonate (HCO3-) and a proton (H+), carbonic anhydrases (CAs), of which five genetically distinct families (alpha - epsilon) are presently known, are fundamental enzymes in all organisms over the phylogenetic tree. In vertebrates, including humans, the 14 different alpha-CA isozymes presently known are involved in a host of physiological and pathological processes and modulation of their activity by means of specific inhibitors or activators leads to important pharmacological responses. CA inhibitors (CAIs) - systemic or topically acting - are clinically used ophthalmologic drugs for the management of glaucoma, cystoid macular oedema and retinopathies of diverse nature, being used alone or in combination therapies with many other agents. Topiramate (TPM) and zonisamide are widely used antiepileptics possessing a complex mechanism of action, in which CA inhibition plays a major role. Other neurological or neuromuscular disorders also make use of agents such as acetazolamide, methazolamide, ethoxzolamide or dichlorophenamide, in addition to the classical CAIs. CA activators on the other hand may lead to novel therapies in the treatment of cognitive disorders. Important advances were recently accomplished in the design of CA V-targeted inhibitors, with potential use as antiobesity agents that inhibit a critical step in lipogenesis in which the mitochondrial isozyme V is involved. Isozymes CA IX and CA XII play important roles in pH regulation, cell adhesion, proliferation and differentiation in hypoxic tumours and constitute conceptually novel targets for anticancer therapies. Indeed, many sulfonamide and sulfamate potent CA IX inhibitors were reported, which may open new vistas for such antitumour therapies. Several CA isozymes are complexed with proteins involved in anion transport, such as anion exchangers (AE1) or Na+/HCO3- cotransporter proteins (NBC1 and NBC3), forming metabolons, in which the enzymatic activity of each protein is enhanced by its companion. The understanding of the biochemical mechanisms involved in such interactions may also lead to important novel pharmacological applications.