Journal
SCIENCE ADVANCES
Volume 6, Issue 45, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abb5924
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Funding
- Gates Cambridge Trust
- Rosalind Franklin Research Fellowship at Newnham College, Cambridge
- UK Research and Innovation (Future Leaders Fellowship) [MR/S033947/1]
- Alzheimer's Society, UK [317, 511]
- Peterhouse, Cambridge
- Swiss National Science Foundation
- Darwin College [P300P2_171219]
- Swiss National Foundation [P2ELP2_162116]
- ARCHER UK National Supercomputing Service under ARCHER Leadership project [e510]
- Engineering and Physical Sciences Research Council (capital grant) [EP/P020259/1]
- Science and Technology Facilities Council
- iNEXT H2020 Programme (EC) [653706]
- Centre for Misfolding Diseases
- INCEPTION project [ANR-16-CONV-0005]
- UKRI [MR/S033947/1] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [P2ELP2_162116] Funding Source: Swiss National Science Foundation (SNF)
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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-beta (A beta) peptide 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 characterize this interaction using biophysical experiments and integrative structural ensemble determination methods. We observe that this molecule increases the conformational entropy of monomeric A beta while decreasing its hydrophobic surface area. We also show that it rescues a Caenorhabditis elegans model of A beta-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.
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