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

• Published in: European journal of medicinal chemistry Vol. 237; p. 114400
• Main Authors: Santoro, Angelo, Grimaldi, Manuela, Buonocore, Michela, Stillitano, Ilaria, Gloria, Antonio, Santin, Matteo, Bobba, Fabrizio, Sublimi Saponetti, Matilde, Ciaglia, Elena, D'Ursi, Anna Maria
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05.07.2022
• Subjects: Alzheimer; Alzheimer Disease - metabolism; Amyloid - chemistry; Amyloid beta-Peptides - chemistry; Amyloid plaques; Amyloidosis; Antibodies - chemistry; Antibody; Aptamers; Biomarkers; Humans; Immunotherapy; Ligands; Peptide design; Peptide Fragments - chemistry; Peptide design; Antibody; Immunotherapy; Aptamers; Biomarkers; Alzheimer; Amyloid plaques
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114400

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. [Display omitted] •Immunotherapy targeting Aβ peptides has excellent potential for treating or preventing Alzheimer's disease (AD).: Several monoclonal antibodies against Aβ(1–42) have been developed, though their production is complex and requires substantial economic investments.•We developed an innovative research approach to design peptide sequences from antibodies targeting different Aβ(1–42)'s epitopes.•CD and NMR based techniques help to probe secondary structure perturbations in Aβ(1–42) in presence of the designed peptides.