Repository logo
 

Infrared nanospectroscopy reveals the molecular interaction fingerprint of an aggregation inhibitor with single Aβ42 oligomers

Published version
Peer-reviewed

Change log

Authors

Ruggeri, Francesco Simone  ORCID logo  https://orcid.org/0000-0002-1232-1907
Habchi, Johnny 
Chia, Sean 
Vendruscolo, Michele  ORCID logo  https://orcid.org/0000-0002-3616-1610

Abstract

Abstract: Significant efforts have been devoted in the last twenty years to developing compounds that can interfere with the aggregation pathways of proteins related to misfolding disorders, including Alzheimer’s and Parkinson’s diseases. However, no disease-modifying drug has become available for clinical use to date for these conditions. One of the main reasons for this failure is the incomplete knowledge of the molecular mechanisms underlying the process by which small molecules interact with protein aggregates and interfere with their aggregation pathways. Here, we leverage the single molecule morphological and chemical sensitivity of infrared nanospectroscopy to provide the first direct measurement of the structure and interaction between single Aβ42 oligomeric and fibrillar species and an aggregation inhibitor, bexarotene, which is able to prevent Aβ42 aggregation in vitro and reverses its neurotoxicity in cell and animal models of Alzheimer’s disease. Our results demonstrate that the carboxyl group of this compound interacts with Aβ42 aggregates through a single hydrogen bond. These results establish infrared nanospectroscopy as a powerful tool in structure-based drug discovery for protein misfolding diseases.

Description

Keywords

Article, /631/45/470/2284, /631/57/2272/2273, /631/57/2265, /631/154, /631/535/1262, /123, /147/136, /147/3, /140/125, /9, article

Journal Title

Nature Communications

Conference Name

Journal ISSN

2041-1723

Volume Title

12

Publisher

Nature Publishing Group UK