Pharmacological Interrogation of the C. elegans Pharyngeal Cuticle Reveals Small Molecule Amyloid Disruptors

Abstract

AbstractUnderstanding how to pharmacologically manipulate amyloids is an essential step towards managing dozens of amyloid-based human diseases. Here, we present a pipeline that yields small molecule antagonists of amyloidogenesis. Screens for small molecules that perturb the development of the nematode C. elegans revealed 24 distinct small molecule scaffolds that crystalize on the non-luminal face of the pharyngeal cuticle. Consistent with the amyloid-like nature of the pharyngeal cuticle, 25% of these scaffolds are known to bind human amyloids with nanomolar affinity. The growing crystals preferentially disrupt the amyloid-like material within the cuticle but leave its chitin-based matrix relatively intact. We screened a collection of drugs and natural products for those that suppress crystal formation and found 45 distinct scaffolds, 33% of which are known amyloid busters. Screening for pharmacological suppressors of crystal formation therefore represents an inexpensive high-throughput in vivo approach that enriches for small molecules with amyloid-busting potential.