Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer's disease.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
05
03
2020
accepted:
22
09
2020
entrez:
5
11
2020
pubmed:
6
11
2020
medline:
15
4
2022
Statut:
epublish
Résumé
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
Identifiants
pubmed: 33148639
pii: 6/45/eabb5924
doi: 10.1126/sciadv.abb5924
pmc: PMC7673680
pii:
doi:
Substances chimiques
Amyloid beta-Peptides
0
Peptide Fragments
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Medical Research Council
ID : MR/S033947/1
Pays : United Kingdom
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
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