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.

doi:10.1101/2020.11.16.384248

bioRxiv · 10.1101/2020.11.16.384248

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.

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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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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.. 2020-11-17. Perphenazine-macrocycle conjugates divert Aβ42 towards non-toxic aggregates by monomer sequestration.. https://doi.org/10.1101/2020.11.16.384248

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