Abstract
Carbonic anhydrases (CAs) are involved in many physiological and pathological .events in organisms all over the phylogenetic tree. Over the last three decades I was involved in unravelling the biochemical basic phenomena connected to these enzymes and in drug design of modulators of their activity (inhibitors and activators). The various approaches I developed were applied to many types of such enzymes and allowed the discovery of many classes of highly isoform-selective inhibitors. This afforded new applications of the inhibitors for the management of hypoxic tumors, neuropathic pain, cerebral ischemia, arthritis, degenerative disorders apart the classical ones connected with these drugs (diuretics, antiglaucoma, antiepileptic and antiobesity action). The study of CA activators showed that these enzymes may represent a crucial family of new targets for improving cognition as well as in therapeutic areas, such as phobias, obsessive-compulsive disorder, generalized anxiety, and post-traumatic stress disorders, for which few efficient therapies are available.
Highlights
I started to work on the metalloenzyme carbonic anhydrase (CAs, EC 4.2.1.1) in 1987 and in the first 15 years of my research the constant leitmotiv was “when will you stop working on such a simple and well-known enzyme”? Such queries came from friends, collaborators and sometimes professors with a much more important experience in chemical/biomedical research than myzelf
The enzyme was already reported in the ‘30s of the last century, its inhibitors were known since the ‘40s and the first clinically used agents based on Carbonic anhydrases (CAs) inhibitors (CAIs) were launched in the 50s [1-6]
(iii) CA inhibitors occluding the entrance to the active site A natural product coumarin was the starting point leading to the discovery of this CA inhibition mechanism [63] as well as a wealth of new types of CAIs belonging to various chemical classes [7381]
Summary
I started to work on the metalloenzyme carbonic anhydrase (CAs, EC 4.2.1.1) in 1987 and in the first 15 years of my research the constant leitmotiv was “when will you stop working on such a simple and well-known enzyme”? Such queries came from friends, collaborators and sometimes professors with a much more important experience in chemical/biomedical research than myzelf. (iii) CA inhibitors occluding the entrance to the active site A natural product coumarin was the starting point leading to the discovery of this CA inhibition mechanism [63] as well as a wealth of new types of CAIs belonging to various chemical classes [7381] When this coumarin was co-crystallized with hCA II, the original compound was not found in the electronic density; instead, its hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative was found bound in a region of the CA active site where inhibitors were never observed to bind, the entrance of the cavity [63] – Figure 1C. CAAs-induced increased ERK phosphorylation which is necessary for memory consolidation, and recent data suggest that these enzymes may represent a crucial family of new targets for improving cognition as well as in therapeutic areas, such as phobias, obsessive-compulsive disorder, generalized anxiety, and post-traumatic stress disorders, for which few efficient therapies are available [85]
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