title: Disease-modifying anti-Alzheimer's drugs: inhibitors of human cholinesterases interfering with β-amyloid aggregation.
abstract: OBJECTIVE
  We recently described multifunctional tools (2a-c) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with Aβ 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 Aβ1-42 self-aggregation, the interference of 2a with the toxic Aβ oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of Aβ toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with Aβ and with the Aβ-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 Aβ oligomerization process thus reducing Aβ oligomers-mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a.
  
  
  CONCLUSIONS
  Converging analytical, biological, and in silico data explained the mechanism of action of 2a on Aβ1-42 oligomers formation and against Aβ-preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.
authors.affiliation: European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Siena, Italy; Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.forename: Samuele
authors.initials: S
authors.lastname: Maramai
authors.forename: Raffaella
authors.initials: R
authors.lastname: Colombo
authors.forename: Laura
authors.initials: L
authors.lastname: Verga
authors.forename: Cristina
authors.initials: C
authors.lastname: Lanni
authors.forename: Ersilia
authors.initials: E
authors.lastname: De Lorenzi
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamponi
authors.forename: Marco
authors.initials: M
authors.lastname: Andreassi
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartolini
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Amyloid beta oligomers; Amyloid beta peptides; Cholinesterase inhibitors; Molecular dynamics; Multifunctional ligands