A rapid in vivo pipeline to identify small molecule inhibitors of amyloid aggregation

Muntasir Kamal, Jessica Knox, Robert I. Horne, Om Shanker Tiwari, Andrew R. Burns, Duhyun Han, Davide Levy, Dana Laor Bar-Yosef, Ehud Gazit, Michele Vendruscolo and Peter J. Roy ()
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Muntasir Kamal: University of Toronto
Jessica Knox: University of Toronto
Robert I. Horne: University of Cambridge
Om Shanker Tiwari: Tel Aviv University
Andrew R. Burns: University of Toronto
Duhyun Han: University of Toronto
Davide Levy: Tel Aviv University
Dana Laor Bar-Yosef: Tel Aviv University
Ehud Gazit: Tel Aviv University
Michele Vendruscolo: University of Cambridge
Peter J. Roy: University of Toronto

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Amyloids are associated with over 50 human diseases and have inspired significant effort to identify small molecule remedies. Here, we present an in vivo platform that efficiently yields small molecule inhibitors of amyloid formation. We previously identified small molecules that kill the nematode C. elegans by forming membrane-piercing crystals in the pharynx cuticle, which is rich in amyloid-like material. We show here that many of these molecules are known amyloid-binders whose crystal-formation in the pharynx can be blocked by amyloid-binding dyes. We asked whether this phenomenon could be exploited to identify molecules that interfere with the ability of amyloids to seed higher-order structures. We therefore screened 2560 compounds and found 85 crystal suppressors, 47% of which inhibit amyloid formation. This hit rate far exceeds other screening methodologies. Hence, in vivo screens for suppressors of crystal formation in C. elegans can efficiently reveal small molecules with amyloid-inhibiting potential.

Date: 2024
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DOI: 10.1038/s41467-024-52480-6

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