Cationic Porphyrins Are Reversible Proteasome Inhibitors

Abstract

The aim of this study is to verify if water-soluble 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 β5 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 β5 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.

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

“…19 Inhibition of the proteasome by hemin and by some designed hydrophilic porphyrins has thus far been documented in biochemical assays only. 20,21 However, if confirmed in biologic systems, this activity may help explain aspects of hemin toxicity. In addition, activation of TLRs and downstream inflammatory signaling, particularly of the TLR-4 pathway, can be triggered by free hemin in some models.…”

Protein Camouflage: Supramolecular Anion Recognition by Ubiquitin

“…[1][2][3][4] The topic is particularly attractive in view of 1) the wide variety of ligands provided by supramolecular chemistry,a nd 2) the continuing challengeo ftargeting protein surfaces, with their unique patchworks of hydrophobic, polar and charged regions. Efforts to approximate protein surfaces with supramolecular ligands have involved calixarenes, [1,[5][6][7][8][9][10][11][12] crown ethers, [13][14][15] curcurbiturils, [16][17][18][19] foldamers, [20][21][22][23] porphyrins [24][25][26][27][28][29][30][31] andt weezers. [2,[31][32][33] Recent attention has focusedo n the cationic side chains of lysine and arginine as potentialt argets that protrudei nvitinglyf rom the protein surface.…”

Porphyrins functionalized by quaternary pyridinium units

“…One should take note of the increasing number of reports concerning porphyrins functionalized by pyridinium units for their useful applications in biological studies [116][117][118][119], as well as for showing other valuable properties [120][121][122].…”