The ubiquitin-proteasome system (UPS) is the major cytosolic proteolytic system in prokaryotes and eukaryotes, [1] with critical functions in cell cycle control, apoptosis, inflammation, transcription, signal transduction, protein quality control, and many other biological processes.[2] The central role of UPS in the cell’s metabolism and in oncogenes process, explains why the compounds that affect this systems, hold important interest. These molecules can be used both as biochemical tools to investigate the process controlled by UPS and as novel drugs to treat the diseases stemmed from UPS alteration.[3] For these reasons, proteasome inhibition has become a new promising strategy in cancer therapeutics. Several compounds, both natural and synthetic, have been found to affect UPS functionality and some proteasome inhibitors are already efficient anticancer drugs. Inspired by this scenario we have found that cationic porphyrins inhibit proteasome peptidase activities. [4] 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.

Cationic porphyrins are reversible Proteasome inhibitors

D'URSO, ALESSANDRO;PURRELLO, Roberto;MILARDI, DANILO
2013

Abstract

The ubiquitin-proteasome system (UPS) is the major cytosolic proteolytic system in prokaryotes and eukaryotes, [1] with critical functions in cell cycle control, apoptosis, inflammation, transcription, signal transduction, protein quality control, and many other biological processes.[2] The central role of UPS in the cell’s metabolism and in oncogenes process, explains why the compounds that affect this systems, hold important interest. These molecules can be used both as biochemical tools to investigate the process controlled by UPS and as novel drugs to treat the diseases stemmed from UPS alteration.[3] For these reasons, proteasome inhibition has become a new promising strategy in cancer therapeutics. Several compounds, both natural and synthetic, have been found to affect UPS functionality and some proteasome inhibitors are already efficient anticancer drugs. Inspired by this scenario we have found that cationic porphyrins inhibit proteasome peptidase activities. [4] 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/304442
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