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

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 A beta peptides have been screened. Peptide molecules have been widely explored, appreciating chemical stability, biocompatibility, and low production cost. More recently, many anti-A beta(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 A beta-antibodies structural data, we followed an innovative research approach to identify short peptide sequences on the model of the binding sites of A beta(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 A beta(1-42) in the soluble monomeric form. Moreover, AFM microscopy imaging shows that WAibH and SYSTPGK are capable of controlling the A beta(1-42) aggregation. The strategy to identify WAibH and SYSTPGK is innovative and can be widely applied for new anti-A beta antibody mimicking peptides.

Automated summary

Alzheimer's disease is a common neurodegenerative disorder characterized by the accumulation of amyloid plaques. Many molecules targeting A beta peptides and anti-A beta monoclonal antibodies have been screened as potential drug candidates. In this study, short peptide sequences were designed based on the binding sites of A beta(1-42)/antibodies, and two peptides, WAibH and SYSTPGK, were identified as mimics of solanezumab and aducanumab, respectively. These antibody-derived peptides were found to interact with soluble A beta(1-42) and control its aggregation.