New Aβ(1-42) ligands from anti-amyloid antibodies: Design, synthesis, and structural interaction

Angelo Santoro, Manuela Grimaldi, Michela Buonocore, Ilaria Stillitano, Antonio Gloria, Matteo Santin, Fabrizio Bobba, Matilde Sublimi Saponetti, Elena Ciaglia, Anna Maria D'Ursi

Research output: Contribution to journalArticlepeer-review


Alzheimer's disease (AD), is the most common neurodegenerative disorder of the aging population resulting in progressive cognitive and functional decline. Accumulation of amyloid plaques around neuronal cells is considered a critical pathogenetic event and, in most cases, a hallmark of the pathology. In the attempt to identify anti-AD drug candidates, hundreds of molecules targeting Aβ peptides have been screened. Peptide molecules have been widely explored, appreciating chemical stability, biocompatibility, and low production cost. More recently, many anti-Aβ(1-42) monoclonal antibodies have been developed, given the excellent potential of immunotherapy for treating or preventing AD. Antibodies are versatile ligands that bind a large variety of molecules with high affinity and specificity; however, their extensive therapeutic application is complex and requires huge economic investments. Novel approaches to identify alternative antibody formats are considered with great interest. In this context, taking advantage of the favorable peptide properties and the availability of Aβ-antibodies structural data, we followed an innovative research approach to identify short peptide sequences on the model of the binding sites of Aβ(1-42)/antibodies. WAibH and SYSTPGK were designed as mimics of solanezumab and aducanumab, respectively. Circular dichroism and nuclear magnetic resonance analysis reveal that the antibody-derived peptides interact with Aβ(1-42) in the soluble monomeric form. Moreover, AFM microscopy imaging shows that WAibH and SYSTPGK are capable of controlling the Aβ(1-42) aggregation. The strategy to identify WAibH and SYSTPGK is innovative and can be widely applied for new anti-Aβ antibody mimicking peptides. [Abstract copyright: Copyright © 2022 Elsevier Masson SAS. All rights reserved.]
Original languageEnglish
Article number114400
Number of pages17
JournalEuropean journal of medicinal chemistry
Publication statusPublished - 23 Apr 2022

Bibliographical note

Funding Information:
The work has been supported by the EC HORIZON2020 project MADIA, contract number 732678 .

Publisher Copyright:
© 2022 Elsevier Masson SAS


  • Aptamers
  • Antibody
  • Amyloid plaques
  • Peptide design
  • Biomarkers
  • Immunotherapy
  • Alzheimer


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