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

A small molecule binds to a disordered protein in its monomeric form, preventing its aggregation linked to Alzheimer’s disease. 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.

• Publication year

  2019

• Venue

  Science Advances

• Publication date

  2019-08-08

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1126/sciadv.abb5924PMID 33148639PMCID 7673680
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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