Editorial [ Carbonic Anhydrases as Drug Targets Executive 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 [1] 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. [2]. 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. The next contribution deals with the carbonic anhydrases belonging to the α- and β-classes recently cloned and characterized from the widespread pathogen Helicobacter pylori, producing a wide range of diseases. In the last years, Nishimori's group [3] demonstrated that both these enzymes are druggable targets. Furthermore, in one of their papers it has been demonstrated for the first time that a non-α-CA, i.e., just the beta-CA from H. pylori, can be a druggable target. At the same level of importance is the report of Krungkrai et al. [4] regarding the presence of several α-CAs in the protozoa causing malaria, belonging to the genus Plasmodium. In several seminal papers, this group reported the cloning, characterization and inhibition studies of one of these enzymes, showing it to be a druggable target. The paper in this issue is just an excellent review of this work, potentially leading to novel antimalarial drugs. A reinvestigation of the sulfonamide diuretics belonging to the thiadiazine and high-ceiling diuretic type provided interesting clues regarding possible new applications of sulfonamide CAIs. Indeed, most of these drugs were discovered in a period when only isoform CA II was wellknown. Retesting these compounds on all the mammalian isozymes, Supuran's group [5] showed that many of these clinically used sulfonamide diuretics act as nanomolar inhibitors against many pharmacologically relevant “new” CA 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. [6] 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. 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. [7]. In fact two mitochondrial CA isoforms, CA VA and CA VB are involved in lipogenesis and their inhibition leads to diminished fatty acid biosynthesis. De Simone's group resolved the X-ray crystallographic structures of many important, clinically used inhibitors with various isozymes, and performed modelling studies regarding their binding to targets which have not been crystallized yet (such as the human CA VA/VB or the human CA IX). Such data are extremely useful for the drug design of inhibitors with various applications, not only as antiobesity agents, but also as antitumor or antiglaucoma drugs.