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TitleCationic Porphyrins Are Reversible Proteasome Inhibitors
AbstractThe aim of this study is to verify if watersoluble porphyrins can be used as proteasome inhibitors. We have found that cationic porphyrins inhibit proteasome peptidase activities much more effectively than the corresponding anionic derivatives. The relevance of electrostatics in driving porphyin-proteasome interactions has been confirmed by the observation that the inhibitory efficiency of the cationic macrocycles decreases with the number of positive substituents. We have also investigated various metalloporphyrins, which differ due to the different propension of the central metal ion toward axial coordination. Our experimental results indicate that the naked cationic porphyrins are the most active in reversibly inhibiting the three main protease activities of the proteasome in the micromolar range. A spectroscopic characterization of porphyrin-proteasome interactions by UV-vis spectra parallels the results of inhibition assays: the higher the inhibitory effect the stronger the spectroscopic variations are. To interpret the action of porphyrins at a molecular level, we have performed calculations evidencing that cationic porphyrins may hinder the access to the canonical proteolytic site on the proteasome ?5 subunit. In particular, an inspection of the top-scoring docking modes shows that the tetracationic porphyrin blocks the catalytic pocket, close to the N termini of the ?5 proteasome subunit, more efficiently than its anionic counterpart. Proteasome inhibition activity of porphyrins unites their known anticancer properties making them suitable as a scaffold for the design of novel multitargeted molecules.
SourceJournal of the American Chemical Society (Online) 134, pp. 10451–10457
KeywordsPorphyrinsproteasome inhibitionmultifunctional molecules
JournalJournal of the American Chemical Society (Online)
EditorAmerican Chemical Society,, Washington, DC, Stati Uniti d'America
Year2012
TypeArticolo in rivista
DOI10.1021/ja300781u |
AuthorsAnna Maria Santoro; Maria Cristina Lo Giudice; Alessandro D'Urso; Rosaria Lauceri; Roberto Purrello; Danilo Milardi
Text213528 2012 10.1021/ja300781u ISI Web of Science WOS WOS 000305716700029 Scopus 2 s2.0 84863490720 Porphyrins proteasome inhibition multifunctional molecules Cationic Porphyrins Are Reversible Proteasome Inhibitors Anna Maria Santoro; Maria Cristina Lo Giudice; Alessandro D Urso; Rosaria Lauceri; Roberto Purrello; Danilo Milardi Anna Maria Santoro, Rosaria Lauceri, Danilo Milardi, IBB CNR, Istituto di Biostrutture e Bioimmagini, UOS di Catania. Maria Cristina Lo Giudice, Alessandro D Urso, Roberto Purrello, Dipartimento di Scienze Chimiche, Universita degli Studi di Catania. The aim of this study is to verify if watersoluble porphyrins can be used as proteasome inhibitors. We have found that cationic porphyrins inhibit proteasome peptidase activities much more effectively than the corresponding anionic derivatives. The relevance of electrostatics in driving porphyin proteasome interactions has been confirmed by the observation that the inhibitory efficiency of the cationic macrocycles decreases with the number of positive substituents. We have also investigated various metalloporphyrins, which differ due to the different propension of the central metal ion toward axial coordination. Our experimental results indicate that the naked cationic porphyrins are the most active in reversibly inhibiting the three main protease activities of the proteasome in the micromolar range. A spectroscopic characterization of porphyrin proteasome interactions by UV vis spectra parallels the results of inhibition assays the higher the inhibitory effect the stronger the spectroscopic variations are. To interpret the action of porphyrins at a molecular level, we have performed calculations evidencing that cationic porphyrins may hinder the access to the canonical proteolytic site on the proteasome 5 subunit. In particular, an inspection of the top scoring docking modes shows that the tetracationic porphyrin blocks the catalytic pocket, close to the N termini of the 5 proteasome subunit, more efficiently than its anionic counterpart. Proteasome inhibition activity of porphyrins unites their known anticancer properties making them suitable as a scaffold for the design of novel multitargeted molecules. 134 Cationic Porphyrins Are Reversible Proteasome Inhibitors reprint pdf JACS_134_10451_2012_all.pdf Articolo in rivista American Chemical Society, 1520 5126 Journal of the American Chemical Society Online Journal of the American Chemical Society Online J. Am. Chem. Soc. Online Journal of the American Chemical Society Online JACS Online rosaria.lauceri LAUCERI ROSARIA annamaria.santoro SANTORO ANNA MARIA danilo.milardi MILARDI DANILO TA.P04.016.004 Ecologia teorica e applicata degli ecosistemi acquatici