Open AccessDisease‐Modifying Anti‐Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with β ‐Amyloid Aggregation
Author(s) -
Brogi Simone,
Butini Stefania,
Maramai Samuele,
Colombo Raffaella,
Verga Laura,
Lanni Cristina,
De Lorenzi Ersilia,
Lamponi Stefania,
Andreassi Marco,
Bartolini Manuela,
Andrisano Vincenza,
Novellino Ettore,
Campiani Giuseppe,
Brindisi Margherita,
Gemma Sandra
Publication year - 2014
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12290
Subject(s) - chemistry , toxicity , fibril , in silico , mechanism of action , amyloid (mycology) , in vitro , biochemistry , biophysics , computational biology , pharmacology , biology , organic chemistry , gene , inorganic chemistry
Summary Aims We recently described multifunctional tools ( 2a – c ) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with A β aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. Methods We determined the inhibitory potency of 2a–c on A β 1–42 self‐aggregation, the interference of 2a with the toxic A β oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of A β toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with A β and with the A β ‐preformed fibrils were computationally analyzed. 2a – c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). Results Our prototypical pluripotent analogue 2a interferes with A β oligomerization process thus reducing A β oligomers‐mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a . Conclusion Converging analytical, biological, and in silico data explained the mechanism of action of 2a on A β 1–42 oligomers formation and against A β ‐preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.