Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.16.384248v1?rss=1 Authors: Ball, S. R., Adamson, J. S., Sullivan, M. A., Zimmermann, M. R., Lo, V., Sanz-Hernandez, M., Jiang, F., Kwan, A. H., Werry, E. L., Knowles, T. P., Kassiou, M., Meisl, G., Todd, M. H., Rutledge, P. R., Sunde, M. Abstract: The amyloid-{beta} peptide, the main protein component of amyloid plaques in Alzheimer's disease, plays a key role in the neurotoxicity associated with the condition through the formation of small toxic oligomer species which mediate the disruption of calcium and glutamate homeostasis. The lack of therapeutic benefit associated with removal of mature amyloid-{beta} fibrils has focused attention on the toxic oligomeric species formed during the process of fibril assembly. Here, we present the design and synthesis of a family of perphenazine-macrocyle conjugates. We find that two-armed perphenazine-cyclam conjugates divert the monomeric form of the amyloid-{beta} peptide away from the amyloidogenic pathway into amorphous aggregates that are not toxic to differentiated SH-SY5Y cells in vitro. This strategy prevents the formation of damaging amyloid oligomers. Kinetic analysis of the effects of these compounds on the assembly pathway, together with NMR spectroscopy, identifies rapid monomer sequestration as the underlying neuroprotective mechanism. The ability to specifically target the monomeric form of amyloid-{beta} allows for further understanding of the impact of the multiple species formed between peptide biogenesis and plaque deposition. The modular, three-dimensional structure of these compounds provides a starting point for the design of more potent modulators of this amyloid-forming peptide, and can be adapted to probe the protein self-assembly pathways associated with other proteinopathies. Copy rights belong to original authors. Visit the link for more info