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

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.

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Publication Details

Journal
Nature Communications
Published
2024-09-27
DOI
https://doi.org/10.1038/s41467-024-52480-6
Citations
5
Primary Topic
Computational Drug Discovery Methods
Type
article
Field-Weighted Citation Impact
1.81

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article

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

Dana Laor Bar‐Yosef, Davide Levy, Om Shanker Tiwari, Michele Vendruscolo et al.
5 citations
Nature Communications
Computational Drug Discovery Methods
1.81
article

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

Dana Laor Bar‐Yosef, Davide Levy, Om Shanker Tiwari, Michele Vendruscolo, Jessica Knox, Duhyun Han, Robert I. Horne, Peter John Roy, Andrew R. Burns, Muntasir Kamal, Ehud Gazit
article en
5 citations

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.

Nature CommunicationsVol. 15(1)
University Health Network (CA), Tel Aviv University (IL), University of Toronto (CA), University of Cambridge (GB), Toronto Western Hospital (CA), Center for NanoScience (DE), Krembil Research Institute
John Templeton Foundation, UK Research and Innovation, Tel Aviv University, National Institutes of Health, Canadian Institutes of Health Research
Openalex Percentile: Top 13%
Computational Drug Discovery Methods
1.81
DOIOpen Access PDFOpenAlex
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