Quantitative Attribution of the Protective Effects of Aminosterols against Protein Aggregates to Their Chemical Structures and Ability to Modulate Biological Membranes
Silvia Errico, Giacomo Lucchesi, Davide Odino, Enass Y. Osman, Roberta Cascella, L. Neri, Claudia Capitini, Martino Calamai, Francesco Bemporad, Cristina Cecchi, William A. Kinney, Denise Barbut, Annalisa Relini, Claudio Canale, Gabriella Caminati, Ryan Limbocker, Michele Vendruscolo, Michael Zasloff, Fabrizio Chiti
Abstract
High Resolution Image Download MS PowerPoint Slide Natural aminosterols are promising drug candidates against neurodegenerative diseases, like Alzheimer and Parkinson, and one relevant protective mechanism occurs via their binding to biological membranes and displacement or binding inhibition of amyloidogenic proteins and their cytotoxic oligomers. We compared three chemically different aminosterols, finding that they exhibited different (i) binding affinities, (ii) charge neutralizations, (iii) mechanical reinforcements, and (iv) key lipid redistributions within membranes of reconstituted liposomes. They also had different potencies (EC 50 ) in protecting cultured cell membranes against amyloid-β oligomers. A global fitting analysis led to an analytical equation describing quantitatively the protective effects of aminosterols as a function of their concentration and relevant membrane effects. The analysis correlates aminosterol-mediated protection with well-defined chemical moieties, including the polyamine group inducing a partial membrane-neutralizing effect (79 ± 7%) and the cholestane-like tail causing lipid redistribution and bilayer mechanical resistance (21 ± 7%), linking quantitatively their chemistry to their protective effects on biological membranes.