Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, we identify a small molecule (10074-G5) capable of binding and sequestering the intrinsically disordered amyloid-β (Aβ) peptide in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterize this interaction using biophysical experiments and integrative structural ensemble determination methods. We observe that this molecule increases the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. We also show that it rescues a Caenorhabditis elegans model of Aβ-associated toxicity, consistent with the mechanism of action identified from the in silico and in vitro studies. These results illustrate the strategy of stabilizing the monomeric states of disordered proteins with small molecules to alter their behavior for therapeutic purposes.

Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer's disease / Heller, G. T.; Aprile, F. A.; Michaels, T. C. T.; Limbocker, R.; Perni, M.; Ruggeri, F. S.; Mannini, B.; Lohr, T.; Bonomi, M.; Camilloni, C.; de Simone, A.; Felli, I. C.; Pierattelli, R.; Knowles, T. P. J.; Dobson, C. M.; Vendruscolo, M.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 6:45(2020), p. eabb5924. [10.1126/SCIADV.ABB5924]

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

de Simone A.;
2020

Abstract

Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, we identify a small molecule (10074-G5) capable of binding and sequestering the intrinsically disordered amyloid-β (Aβ) peptide in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterize this interaction using biophysical experiments and integrative structural ensemble determination methods. We observe that this molecule increases the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. We also show that it rescues a Caenorhabditis elegans model of Aβ-associated toxicity, consistent with the mechanism of action identified from the in silico and in vitro studies. These results illustrate the strategy of stabilizing the monomeric states of disordered proteins with small molecules to alter their behavior for therapeutic purposes.
2020
Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer's disease / Heller, G. T.; Aprile, F. A.; Michaels, T. C. T.; Limbocker, R.; Perni, M.; Ruggeri, F. S.; Mannini, B.; Lohr, T.; Bonomi, M.; Camilloni, C.; de Simone, A.; Felli, I. C.; Pierattelli, R.; Knowles, T. P. J.; Dobson, C. M.; Vendruscolo, M.. - In: SCIENCE ADVANCES. - ISSN 2375-2548. - 6:45(2020), p. eabb5924. [10.1126/SCIADV.ABB5924]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/828845
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