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      Disease‐Modifying Anti‐Alzheimer's Drugs: Inhibitors of Human Cholinesterases Interfering with β‐Amyloid Aggregation

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          Summary

          Aims

          We recently described multifunctional tools ( 2ac) 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. 2ac 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.

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          Author and article information

          Journal
          CNS Neurosci Ther
          CNS Neurosci Ther
          10.1111/(ISSN)1755-5949
          CNS
          CNS Neuroscience & Therapeutics
          John Wiley and Sons Inc. (Hoboken )
          1755-5930
          1755-5949
          17 June 2014
          July 2014
          : 20
          : 7 , Interdisciplinary Chemical Approaches for Neuropathology Guest Editors: Giuseppe Di Giovanni and Rona Ramsay ( doiID: 10.1111/cns.2014.20.issue-7 )
          : 624-632
          Affiliations
          [ 1 ] European Research Centre for Drug Discovery and Development (NatSynDrugs) University of Siena Siena Italy
          [ 2 ] Dipartimento di Biotecnologie Chimica e Farmacia University of Siena Siena Italy
          [ 3 ] Dipartimento di Scienze del Farmaco University of Pavia Pavia Italy
          [ 4 ] Department of Pathology, Fondazione IRCCS, Policlinico S. Matteo University of Pavia Pavia Italy
          [ 5 ] Department of Pharmacy and Biotechnology University of Bologna Bologna Italy
          [ 6 ] Department for Life Quality Studies University of Bologna Rimini Italy
          [ 7 ] Dipartimento di Farmacia University of Napoli Federico II Napoli Italy
          Author notes
          [*] [* ] Correspondence

          Stefania Butini, European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

          Tel.: +0039 0577 234161;

          Fax: +0039 0577 234254;

          E‐mail: butini3@ 123456unisi.it

          and

          Dipartimento di Biotecnologie, Chimica e Farmacia, University of Siena, via Aldo Moro 2, 53100 Siena, Italy

          Article
          PMC6493034 PMC6493034 6493034 CNS12290
          10.1111/cns.12290
          6493034
          24935788
          213fa4d1-1639-4b05-af51-34f49ef6dd05
          © 2014 John Wiley & Sons Ltd
          History
          : 13 February 2014
          : 18 April 2014
          : 30 April 2014
          Page count
          Pages: 9
          Categories
          Special Issue Article
          Original Articles
          Custom metadata
          2.0
          cns12290
          July 2014
          Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:02.05.2019

          Amyloid beta peptides,Cholinesterase inhibitors,Amyloid beta oligomers,Multifunctional ligands,Molecular dynamics,Alzheimer's disease

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