Quantitative Attribution of the Protective Effects of Aminosterols against Protein Aggregates to Their Chemical Structures and Ability to Modulate Biological Membranes

Year: 2023

Authors: Errico S., Lucchesi G., Odino D., Osman EY., Cascella R., Neri L., Capitini C., Calamai M., Bemporad F., Cecchi C., Kinney WA., Barbut D., Relini A., Canale C., Caminati G., Limbocker R., Vendruscolo M., Zasloff M., Chiti F.

Autors Affiliation: Univ Florence, Dept Expt & Clin Biomed Sci, Sect Biochem, I-50134 Florence, Italy; Univ Cambridge, Ctr Misfolding Dis, Dept Chem, Cambridge CB2 1EW, England; Univ Florence, Dept Chem Ugo Schiff, CSGI, I-50019 Sesto Fiorentino, Italy; Univ Genoa, Dept Phys, I-16146 Genoa, Italy; Tanta Univ, Fac Pharm, Dept Pharmacol & Toxicol, Arab Republ Egypt, Tanta 31527, Egypt; European Lab Nonlinear Spect LENS, I-50019 Sesto Fiorentino, Italy; Univ Florence, Dept Phys & Astron, I-50019 Sesto Fiorentino, Italy; Natl Res Council Italy CNR, Natl Inst Opt, I-50125 Florence, Italy; Enterin Res Inst Inc, Philadelphia, PA 19103 USA; US Mil Acad, Dept Chem & Life Sci, West Point, NY 10996 USA; Georgetown Univ, Sch Med, MedStar Georgetown Transplant Inst, Washington, DC 20007 USA.

Abstract: Natural aminosterols are promising drug candidates againstneurodegenerativediseases, like Alzheimer and Parkinson, and one relevant protectivemechanism occurs via their binding to biological membranes and displacementor binding inhibition of amyloidogenic proteins and their cytotoxicoligomers. We compared three chemically different aminosterols, findingthat they exhibited different (i) binding affinities, (ii) chargeneutralizations, (iii) mechanical reinforcements, and (iv) key lipidredistributions within membranes of reconstituted liposomes. Theyalso had different potencies (EC50) in protecting culturedcell membranes against amyloid-& beta; oligomers. A global fittinganalysis led to an analytical equation describing quantitatively theprotective effects of aminosterols as a function of their concentrationand relevant membrane effects. The analysis correlates aminosterol-mediatedprotection with well-defined chemical moieties, including the polyaminegroup inducing a partial membrane-neutralizing effect (79 & PLUSMN; 7%)and the cholestane-like tail causing lipid redistribution and bilayermechanical resistance (21 & PLUSMN; 7%), linking quantitatively theirchemistry to their protective effects on biological membranes.

Journal/Review: JOURNAL OF MEDICINAL CHEMISTRY

Volume: 66 (14)      Pages from: 9519  to: 9536

More Information: This research was funded by the Regione Toscana (FAS-Salute 2017, project PRAMA); the University of Florence (Fondi di Ateneo). MIUR-Italy Progetto Dipartimenti di Eccellenza 2018-2022 allocated to Department of Chemistry Ugo Schiff (Florence), Department of Experimental and Clinical Biomedical Sciences Mario Serio (Florence) and Department of Physics (Genoa). The project has received funding also from Horizon 2020 research and innovation programme, Integrated Initiative of European Laser Research Infrastructures – LASERLAB-EUROPE, Grant Agreement number 871124; and from the Italian Ministry for Education within the framework of the Euro-Bioimaging Italian Node (ESFRI research infrastructure). We thank Riccardo Ferrando for help in force map data elaboration. We thank Alfonso de Simone for providing aS.
KeyWords: Alpha-synuclein Aggregation; Squalamine; Oligomers; Toxicity; Behavior; Shark
DOI: 10.1021/acs.jmedchem.3c00182

Citations: 4
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