{"doi":"10.1101/2022.04.11.487937","title":"A Rapid <i>in vivo</i> Pipeline to Identify Small Molecule Inhibitors of Amyloid Aggregation","abstract":"Abstract Amyloids are associated with over 50 human diseases and have inspired significant effort to identify small molecule remedies. Here, we present a novel in vivo platform that efficiently yields small molecule disruptors 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. Furthermore, we found that amyloid fibrils can seed small molecule crystal formation in vitro . These observations suggest that small molecule crystals are seeded by the cuticle’s amyloid-like material. We asked whether this phenomenon could be exploited to identify additional molecules that interfere with the ability of amyloids to seed higher-order structures. We screened 2560 compounds and identified 85 crystal suppressors, which we found to be 10-fold enriched in known amyloid disruptors relative to a random set. Of the uncharacterized suppressors, we found 25% to inhibit Ab42 fibril nucleation and/or extension in vitro , which is a hit rate that far exceeds other screening methodologies. Hence, screens for suppressors of crystal formation can efficiently reveal small molecules with amyloid-disrupting potential.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":306815,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9481,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":583538,"name":"Jessica Knox","orcid":"0000-0003-1465-5852","position":1,"is_corresponding":false},{"id":1001485,"name":"Robert I. Horne","orcid":null,"position":2,"is_corresponding":false},{"id":1001486,"name":"Om Shanker Tiwari","orcid":null,"position":3,"is_corresponding":false},{"id":1001160,"name":"Andrew R. Burns","orcid":"0000-0002-8966-1280","position":4,"is_corresponding":false},{"id":1001487,"name":"Duhyun Han","orcid":null,"position":5,"is_corresponding":false},{"id":1001488,"name":"Dana Laor Bar-Yosef","orcid":null,"position":6,"is_corresponding":false},{"id":225457,"name":"Ehud Gazit","orcid":"0000-0001-5764-1720","position":7,"is_corresponding":false},{"id":212198,"name":"Michele Vendruscolo","orcid":null,"position":8,"is_corresponding":false},{"id":583539,"name":"Peter J. Roy","orcid":"0000-0003-2959-2276","position":9,"is_corresponding":false},{"id":866308,"name":"Muntasir Kamal","orcid":"0000-0002-5354-5747","position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-19T00:32:52.703737Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}