| Autor: |
Persico M; Department of Pharmacy, University of Naples 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy., Santoro AM; National Research Council, Institute of Crystallography, Sede Secondaria di Catania, Via Paolo Gaifami 18, 95126 Catania, Italy., D'Urso A; Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy., Milardi D; National Research Council, Institute of Crystallography, Sede Secondaria di Catania, Via Paolo Gaifami 18, 95126 Catania, Italy., Purrello R; Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy., Cunsolo A; Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy., Gobbo M; Department of Chemical Sciences, University of Padua, Via F. Marzolo, 1, 35131 Padova, Italy., Fattorusso R; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Via Vivaldi 43, 81100 Caserta, Italy., Diana D; National Research Council, Insitute of Biostructures and Bioimaging, Via Mezzocannone 16, 80134 Napoli, Italy., Stefanelli M; Department of Chemical Sciences and Technologies, University of Roma Tor Vergata, Via della Ricerca Scientifica, 00133 Roma, Italy., Tundo GR; Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133 Roma, Italy., Sbardella D; IRCCS-Fondazione BIETTI, Rome, Italy., Coletta M; IRCCS-Fondazione BIETTI, Rome, Italy., Fattorusso C; Department of Pharmacy, University of Naples 'Federico II', Via D. Montesano 49, 80131 Napoli, Italy. |
| Abstrakt: |
Cationic porphyrins exhibit an amazing variety of binding modes and inhibition mechanisms of 20S proteasome. Depending on the spatial distribution of their electrostatic charges, they can occupy different sites on α rings of 20S proteasome by exploiting the structural code responsible for the interaction with regulatory proteins. Indeed, they can act as competitive or allosteric inhibitors by binding at the substrate gate or at the grooves between the α subunits, respectively. Moreover, the substitution of a charged moiety in the peripheral arm with a hydrophobic moiety revealed a "new" 20S functional state with higher substrate affinity and catalytic efficiency. In the present study, we expand our structure-activity relationship (SAR) analysis in order to further explore the potential of this versatile class of 20S modulators. Therefore, we have extended the study to additional macrocyclic compounds, displaying different structural features, comparing their interaction behavior on the 20S proteasome with previously investigated compounds. In particular, in order to evaluate how the introduction of a peptidic chain can affect the affinity and the interacting mechanism of porphyrins, we investigate the MTPyApi, a porphyrin derivatized with an Arg-Pro-rich antimicrobial peptide. Moreover, to unveil the role played by the porphyrin core, this was replaced with a corrole scaffold, a "contracted" version of the tetrapyrrolic ring due to the lack of a methine bridge. The analysis has been undertaken by means of integrated kinetic, Nuclear Magnetic Resonance, and computational studies. Finally, in order to assess a potential pharmacological significance of this type of investigation, a preliminary attempt has been performed to evaluate the biological effect of these molecules on MCF7 breast cancer cells in dark conditions, envisaging that porphyrins may indeed represent a powerful tool for the modulation of cellular proteostasis. |
