Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 1A8, Canada.
The Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
Nat Commun. 2024 Sep 27;15(1):8311. doi: 10.1038/s41467-024-52480-6.
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.
淀粉样蛋白与 50 多种人类疾病有关，并激发了人们寻找小分子治疗方法的巨大努力。在这里，我们提出了一个体内平台，能够有效地产生抑制淀粉样蛋白形成的小分子抑制剂。我们之前发现了一些小分子，它们通过在富含淀粉样物质的咽部表皮形成穿透细胞膜的晶体来杀死线虫 C. elegans。我们在这里表明，其中许多分子是已知的淀粉样蛋白结合物，它们在咽部的晶体形成可以被淀粉样蛋白结合染料阻断。我们想知道这种现象是否可以用来鉴定干扰淀粉样蛋白形成高级结构的分子。因此，我们筛选了 2560 种化合物，发现了 85 种晶体抑制剂，其中 47%抑制了淀粉样蛋白的形成。这个命中率远远超过了其他筛选方法。因此，在体内筛选 C. elegans 中晶体形成的抑制剂可以有效地发现具有淀粉样蛋白抑制潜力的小分子。
