Editorial [Hot Topic: Carbonic Anhydrase Inhibitors (Guest Editor: Claudiu T. Supuran)]

Carbonic anhydrases (CAs), the metalloenzymes that catalyze the conversion between carbon dioxide and bicarbonate, continue to be surprising targets, as many exciting new discoveries related to them emerge constantly. This is indeed unprecedented as these are quite “old” enzymes, which were discovered in 1933, and thoroughly investigated since then as drug targets. Furthermore, their inhibitors are in clinical use since the 50s. However, in the last years, a host of interesting reports were made regarding the catalytic/inhibition mechanism as well as isolation/characterization of new isozymes belonging to this family, as well as of CAs of non-vertebrate origin. The first paper in this issue of the Journal dedicated to these enzymes and their inhibitors, represents an overview of CAs as drug targets. In fact, among the 16 isoforms known up to now in mammals, 12 catalytically active ones seem to be appropriate for designing inhibitors with various therapeutic applications (only CA III seems to remain an orphan target). In addition, many carbonic anhydrases isolated from other organisms were recently shown to be possible targets for the drug design, such as the α-CAs from Plasmodium falciparum and Helicobacter pylori, the β-CAs from Mycobacterium tuberculosis, Candida albicans, Cryptococcus neoformans, etc. Work is in progress in many laboratories for developing specific inhibitors targeting these enzymes, that would lead to conceptually novel therapies. An exhaustive review regarding the design of such inhibitors possessing different metal-binding functions than the classical sulfonamide one is then presented by Winum et al. The last years saw many relevant developments in this field with the report of several interesting classes of such derivatives, among which the sulfamates, sulfamides, substituted sulfonamides/sulfamides, etc., as well as a detailed X-ray crystallographic dscription of their interactions with various pharmacologically relevant isoforms. Historically, in addition to their well-known role for the development of diuretics, the CA inhibitors were mainly used as antiglaucoma agents. The review by Mincione et al. in this issue presents up-to-date data regarding the ophthalmologic use of systemically- and topically-acting CA inhibitors, as well as some drug design studies reported ultimately, which substantially extended the current knowledge in obtaining water-soluble such derivatives, potentially useful not only in the treatment of glaucoma but also for the management of macular degeneration. CA inhibitors were also used as antiepileptic drugs, but with less fortune. Indeed, the classical derivatives, acetazolamide and methazolamide, showed reduced utility in the treatment of seizure, as presented thoroughly in the review of Thiry et al., regarding the anticonvulsants belonging to this class of pharmacological agents. However, the last years saw the discovery of many CA isoforms present in the brain and a somehow better understanding of their role in this organ. Furthermore, some newer antiepileptics, such as topiramate and zonisamide also show substantial CA inhibitory activity, although it is unclear to what extent this activity is essential for their anticonvulsant effects, since these drugs possess a complex mechanism of action. Probably the most unexpected applications of the CA inhibitors are those regarding the diagnosis and treatment of tumors. This very important and dynamic research field is reviewed in the excellent paper of Pastorekova et al., the discoverer of the first tumor-associated CA isozyme, CA IX. In several seminal papers from her group, it has recently been demonstrated that CA IX (and probably also CA XII, the other tumor-associated isozyme) is overexpressed in hypoxic tumors being involved in tumor acidification processes which lead to metastatic spread and non-responsiveness to chemotherapeutic agents/radiation treatment. Furthermore, the same group demonstrated that sulfonamide CA IX-selective inhibitors may revert these processes, opening the way to conceptually novel anticancer therapies and diagnostic tools based on CA IX inhibitors. In the last years, there are also encouraging reports linking CA inhibitors to novel antiobesity therapies, field reviewed in a nice paper by De Simone et al.