Perphenazine-macrocycle conjugates divert Aβ42 towards non-toxic aggregates by monomer sequestration.
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.
Show abstract
Alzheimers disease is imposing a growing social and economic burden worldwide and effective therapies are required. Strategies aimed at the removal of fibrillar plaques formed by the amyloid-{beta} peptide have not proved therapeutic and the focus has shifted to approaches that target the cytotoxic oligomeric amyloid-{beta} species that are populated before fibrils are deposited. We have designed and synthesized perphenazine-cyclam conjugates that specifically and rapidly bind to the monomeric form of A{beta}42, reducing the production of both cytotoxic oligomers and amyloid fibrils. We have applied detailed kinetic analysis and NMR spectroscopy to show that the perphenazine-cyclam conjugates divert the A{beta}42 monomer into amorphous aggregates that are not toxic to differentiated SH-SY5Y cells in vitro. Unlike most other amyloid inhibitors studied to date, these conjugates inhibit oligomer and fibril assembly even in the presence of pre-formed fibrillar seeds, demonstrating that they act through a monomer sequestration mechanism. These modular, three-dimensional conjugates therefore effectively prevent monomer-dependent secondary nucleation, the autocatalytic process that generates the majority of toxic oligomers.
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