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bioRxiv · 10.1101/729392

Small molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer’s disease

Heller, G. T.·Aprile, F. A.·Michaels, T. C.·Limbocker, R.·Perni, M.·Ruggeri, F. S.·Mannini, B.·Lohr, T.·Bonomi, M.·De Simone, A.·Felli, I. C.·Pierattelli, R.·Knowles, T. P.·Dobson, C. M.·Vendruscolo, M.
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Abstract

Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that has been shown to modify the properties of their monomeric states. Here, we identify a small molecule capable of binding and sequestering the amyloid-{beta} peptide (A{beta}) in its monomeric, soluble state. Our analysis reveals that this compound interacts with A{beta} and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterise this interaction using biophysical experiments and integrative structural ensemble determination methods. We thus observe that this small molecule has the remarkable effect of increasing the conformational entropy of monomeric A{beta} while decreasing its hydrophobic surface area. We then show that this small molecule rescues a Caenorhabditis elegans model of A{beta}-associated toxicity in a manner consistent with the mechanism of action identified from the in silico and in vitro studies. These results provide an illustration of the strategy of targeting the monomeric states of disordered proteins with small molecules to alter their behaviour for therapeutic purposes.

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Heller, G. T., Aprile, F. A., Michaels, T. C., Limbocker, R., Perni, M., Ruggeri, F. S., Mannini, B., Lohr, T., Bonomi, M., De Simone, A., Felli, I. C., Pierattelli, R., Knowles, T. P., Dobson, C. M., Vendruscolo, M.. 2019-08-08. Small molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer’s disease. https://doi.org/10.1101/729392

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