title: A Divalent PAMAM-Based Matrix Metalloproteinase/Carbonic Anhydrase Inhibitor for the Treatment of Dry Eye Syndrome.
abstract: Synthetic sulfonamide derivatives are a class of potent matrix metalloproteinase inhibitors (MMPI) that have potential for the treatment of diseases related to uncontrolled expression of these enzymes. The lack of selectivity of the large majority of such inhibitors, leading to the inhibition of MMPs in tissues other than the targeted one, has dramatically reduced the therapeutic interest in MMPIs. The recent development of efficient drug delivery systems that allow the transportation of a selected drug to its site of action has opened the way to new perspectives in the use of MMPIs. Here, a PAMAM-based divalent dendron with two sulfonamidic residues was synthesized. This nanomolar inhibitor binds to the catalytic domain of two MMPs as well as to the transmembrane human carbonic anhydrases (hCAs) XII, which is present in the eye and considered an antiglaucoma target. In the animal model of an experimental dry eye, no occurrence of dotted staining in eyes treated with our inhibitor was observed, indicating no symptoms of corneal desiccation.
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Richichi
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Baldoneschi
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 33, 56126, Pisa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Burgalassi
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.|CERM, University of Florence, via Sacconi 6, 50019, Sesto Fiorentino, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fragai
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Vullo
authors.affiliation: Department of Pharmacy, Faculty of Pharmacy, Bezmialem Vakif University, Vatan Caddesi, 34093, Fatih, Istanbul, Turkey.
authors.forename: A
authors.initials: A
authors.lastname: Akdemir
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Dragoni
authors.affiliation: CERM, University of Florence, via Sacconi 6, 50019, Sesto Fiorentino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Louka
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mamusa
authors.affiliation: Department of Pharmacy, University of Pisa, via Bonanno 33, 56126, Pisa, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Monti
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Berti
authors.affiliation: Department of Pharmacy, University of Napoli "Federico II" via Montesano 49, 80131, Napoli, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Pharmacy, University of Napoli "Federico II" via Montesano 49, 80131, Napoli, Italy.
authors.forename: G
authors.initials: G
authors.lastname: De Rosa
authors.affiliation: NEUROFARBA Department, University of Florence, via U. Schiff 6, Sesto Fiorentino, Italy.
authors.forename: C T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Department of Chemistry "Ugo Schiff", University of Florence, via della Lastruccia 3-13, 50019, Sesto Fiorentino, Italy. cristina.nativi@unifi.it.|CERM, University of Florence, via Sacconi 6, 50019, Sesto Fiorentino, Italy. cristina.nativi@unifi.it.
authors.forename: C
authors.initials: C
authors.lastname: Nativi
mesh_terms: D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D016503:Drug Delivery Systems; D015352:Dry Eye Syndromes / Q000188:drug therapy*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases
keywords: dendrimers; drug delivery; drug discovery; inhibitors; metalloproteins