Cationic Porphyrins Are Reversible Proteasome Inhibitors
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- 作者：Anna Maria Santoro ; Maria Cristina Lo Giudice ; Alessandro D鈥橴rso ; Rosaria Lauceri ; Roberto Purrello ; Danilo Milardi
- 刊名：The Journal of the American Chemical Society
- 出版年：2012
- 出版时间：June 27, 2012
- 年：2012
- 卷：134
- 期：25
- 页码：10451-10457
- 全文大小：359K
- 年卷期：v.134,no.25(June 27, 2012)
- ISSN：1520-5126
文摘
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鈥損roteasome 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鈥損roteasome interactions by UV鈥搗is 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 尾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 尾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.