PT  - JOURNAL ARTICLE
AU  - Sean Chia
AU  - Z. Faidon Brotzakis
AU  - Robert I. Horne
AU  - Andrea Possenti
AU  - Benedetta Mannini
AU  - Rodrigo Cataldi
AU  - Magdalena Nowinska
AU  - Roxine Staats
AU  - Sara Linse
AU  - Tuomas P. J. Knowles
AU  - Johnny Habchi
AU  - Michele Vendruscolo
TI  - Structure-based discovery of small molecule inhibitors of the autocatalytic proliferation of α-synuclein aggregates
AID  - 10.1101/2021.12.05.471256
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.05.471256
4099  - http://biorxiv.org/content/early/2021/12/05/2021.12.05.471256.short
4100  - http://biorxiv.org/content/early/2021/12/05/2021.12.05.471256.full
AB  - The presence of amyloid fibrils of α-synuclein is closely associated with Parkinson’s disease and related synucleinopathies. It is still very challenging, however, to systematically discover small molecules that prevent the formation of these aberrant aggregates. Here, we describe a structure-based approach to identify small molecules that specifically inhibit the surface-catalyzed secondary nucleation step in the aggregation of α-synuclein by binding to the surface of the amyloid fibrils. The resulting small molecules are screened using a combination of kinetic and thermodynamic assays for their ability to bind α-synuclein fibrils and prevent the further generation of toxic oligomers. This study demonstrates that the combination of structure-based and kinetic-based drug discovery methods can lead to the identification of small molecules that selectively inhibit the autocatalytic proliferation of α-synuclein aggregates.Competing Interest StatementThe authors have declared no competing interest.