Cautionary Tale On Amyloid Inhibitors

Amyloid inhibitors' tendency to aggregate may be the key to their ability to block amyloid polymerization, according to a new study (Nat. Chem. Biol., DOI: 10.1038/nchembio.65). The finding provides a cautionary tale for the development of drugs for Alzheimer's and other neurodegenerative diseases associated with the polymerization of proteins into amyloid fibrils. Brian K. Shoichet, Brian Y. Feng, and coworkers at the University of California, San Francisco, show that eight small molecules known to form colloidal aggregates in solution actually inhibit fibril formation. What's more, they found evidence that three previously identified amyloid inhibitors—the flavonoid baicalein, 4,5-dianilinophthalimide, and the hydroxyquinoline clioquinol—form similar colloidal aggregates. Colloidal aggregates nonspecifically inhibit their protein prey by physical sequestration. The mechanism by which the aggregation-prone amyloid inhibitors act appears to be similar, they report.