Contact person: Giuseppina De Simone, giuseppina.desimone
cnr.itActors: Martina Buonanno, martina.buonanno
cnr.it, Simona Maria Monti, marmontiunina.it, Emma Langella, emma.langellacnr.it, Anna Di Fiore, anna.difiorecnr.it, Katia D'Ambrosio, katia.dambrosiocnr.it, Giuseppina De Simone, giuseppina.desimonecnr.it, Vincenzo Alterio, vincenzo.alterio@ibb.cnr.it, Carbonicanhydrases (CAs) are ubiquitous enzymes, which catalyze the inter-conversion ofthe carbon dioxide in bicarbonate ion. In humans fifteen isoforms have beenidentified, whose absence or malfunctioning can cause several pathologies.Consequently, in the last years CA isozymes have become interesting targets forpharmaceutical research. CA IX is a peculiar member of the human CA family. Itis a membrane protein consisting of a N-terminal proteoglycan-like domain (PG),an extracellular CA catalytic domain, a trans-membrane helical segment (TM) anda short intracytoplasmic tail (IC). The first region represents a uniquefeature that appears to endow CA IX with the capacity to act inprotein-mediated cell adhesion events, while the catalytic domain, catalyzingthe reversible hydration of CO 2 , contributes to pH regulation.Recent experiments demonstrated an aberrant increase in the expression of thisenzyme in chronic hypoxia and during development of various human carcinomas.It has also been suggested that CA IX contributes to tumorigenesis via itsparticipation in the control of cell adhesion and in pH regulation. It is clearfrom these observations that CA IX represents an interesting target for thedevelopment of new diagnostics and therapeutics in the tumor treatment. Thus,final aim of this research activity is the obtainment of molecules able tointeract selectively with human CA IX and consequently to modulate itsactivities. Two different approaches are used. On one side, starting from theknowledge of the structure of the CA IX catalytic domain alone and in complexwith inhibitors, a structure-based drug design approach is used to developmolecules able to modulate the enzyme catalytic activity; on the other side,after the identification of the CA IX interacting protein partners, smallpeptidic or peptidic-like molecules are developed to regulate these interactions.
De SimoneG. Targeted treatment of anaerobic cancer. Patent evaluation of S2016279084 andUS2017056350. Expert Opin Ther Pat. 2019 Jan;29(1):1
SupuranCT, Alterio V, Di Fiore A, D' Ambrosio K, Carta F, Monti SM, De Simone G.
Inhibitionof carbonic anhydrase IX targets primary tumors, metastases, and cancer stemcells: Three for the price of one.
MedRes Rev. 2018 Sep;38(6):1799
Langella E, Buonanno M, Vullo D, Dathan N, Leone M,Supuran CT, De Simone G, Monti SM.
Biochemical, biophysical and molecular dynamicsstudies on the proteoglycan-like domain of carbonic anhydrase IX. Cell Mol LifeSci. 2018 Sep;75(17):3283
BuonannoM, Langella E, Zambrano N, Succoio M, Sasso E, Alterio V, Di Fiore A,Sandomenico A, Supuran CT, Scaloni A, Monti SM, De Simone G. Disclosing theInteraction of Carbonic Anhydrase IX with Cullin-Associated NEDD8-DissociatedProtein 1 by Molecular Modeling and Integrated Binding Measurements. ACS ChemBiol. 2017 Jun 16;12(6):1460
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.
Crystalstructure of the catalytic domain of the tumor-associated human carbonicanhydrase IX. Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16233
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