Identification of Broad-Spectrum Inhibitors Targeting Multiple Amyloidogenic Proteins Using Functional Group-Based...

Amyloidosis comprises a spectrum of protein misfolding disorders characterized by the aggregation of diverse amyloidogenic proteins into cytotoxic fibrillar structures. Due to the conserved β-sheet-rich architecture of fibrils across various amyloid species, pan-amyloid therapeutics present a promising strategy for simultaneously targeting multiple amyloidogenic proteins. In this study, four representative amyloidogenic proteins-amyloid β, serum amyloid A1, islet amyloid polypeptide, and transthyretin-were selected as targets. From a library of 10,272 small molecules, five functional groups were identified as critical contributors to high-affinity binding. Utilizing these functional groups, potential compounds capable of binding to all four amyloidogenic proteins were further screened. This functional group-based screening workflow not only validates the effectiveness of functional group-driven screening in multitarget drug discovery but also facilitates the efficient identification of candidate pan-amyloid binding compounds. Furthermore, these findings provide valuable insights into the development of pan-amyloid therapeutic strategies.