Description: Selectivity of enzyme inhibitors for closely related isoforms of the same enzymatic class is particularly important for the drug design of either pharmacological tools or potential drugs. An interesting example is offered by the family of Carbonic Anhydrases (CAs, EC 4. 2. 1. 1), which are involved in a variety of physiological and pathological processes of remarkable interest. CAs are ubiquitous metallo-enzymes, acting as catalysts in the reversible hydration of CO2 to HCO3-and H+. These enzymes are present in prokaryotes and eukaryotes and are encoded by five distinct evolutionarily non-related gene families: alfa, beta, gamma, delta and zeta. All human CAs (hCAs) belong to the alfa-class; up to now, fifteen isozymes have been identified, among which twelve are catalytically active (CAs I-IV, CAs VA-VB, CAs VI-VII, CA IX and CAs XII-XIV), whereas the CA-related proteins (CARPs) VIII, X and XI are devoid of any catalytic activity. CA isozymes widely differ in their kinetic properties, response to inhibitors, pattern of expression in various tissues and cellular localization. Indeed CA I, II, III, VII and XIII reside in the cytosol, CA IV, IX, XII and XIV are associated with the cell membrane, CA VA and VB occur in mitochondria, whereas CA VI is secreted in saliva and milk. In the last years, CA isozymes have become an interesting target for the design of inhibitors or activators with biomedical applications. Indeed, several studies demonstrated important roles of CAs in a variety of physiological processes and showed that abnormal levels and/or activities of these enzymes have been often associated with different human diseases, such as glaucoma, osteoporosis, neurological disorders, cancer, etc. Originally CA inhibitors (CAIs) were clinically used mainly as diuretics, anti-glaucoma and anti-epileptics, while the novel generation compounds are undergoing clinical investigation as anti-obesity or anti-tumor drugs/diagnostic tools. However, none of the currently clinically used CA inhibitors shows selectivity for a specific isozyme. Thus, developing isozyme-specific CA inhibitors should be highly beneficial in obtaining novel classes of drugs devoid of various undesired side-effects. Main objective of this activity is the development of isoform-specific CA inhibitors. At this aim structural characterization of new CA isoforms and/or their complexes with known inhibitors will be performed. The obtained structural information, will be used for the rational drug design of more selective ligands, which will be then synthesized and characterized for their inhibitory features. The most potent and selective molecules will be co-crystallized again in complex with the target isoform to confirm the design hypothesis and to improve their features. Further derivatized molecules containing proper tags with potential use as diagnostic and therapeutic tools will be designed and synthesized.
Selected papers: 1. Supuran CT, Di Fiore A, Alterio V, Monti SM, De Simone G. Curr Pharm Des. 2010; 16: 3246-54. 2. Alterio V, Hilvo M, Di Fiore A, Supuran CT, Pan P, Parkkila S, Scaloni A, Pastorek J, Pastorekova S, Pedone C, Scozzafava A, Monti SM, De Simone G. Proc Natl Acad Sci U S A. 2009; 106: 16233-8. 3. Vitale RM, Alterio V, Innocenti A, Winum JY, Monti SM, De Simone G, Supuran CT. J Med Chem. 2009; 52: 5990-8. 4. De Simone G, Supuran CT. Biochim Biophys Acta. 2010 Feb; 1804 (2): 404-9. 5. Supuran CT, Di Fiore A, De Simone G. Expert Opin Emerg Drugs. 2008; 13: 383-92. 6. De Simone G, Di Fiore A, Supuran CT. Curr Pharm Des. 2008; 14: 655-60. 7. De Simone G, Supuran CT. Curr Top Med Chem. 2007; 7: 879-84. 8. De Simone G, Vitale RM, Di Fiore A, Pedone C, Scozzafava A, Montero JL, Winum JY, Supuran CT. J Med Chem. 2006; 49: 5544-51. 9. Alterio V, Vitale RM, Monti SM, Pedone C, Scozzafava A, Cecchi A, De Simone G, Supuran CT. J Am Chem Soc. 2006; 128: 8329-35
Carbonic Anhydrase family as target for rational drug design