Discovery of amyloid binders as chemical chaperone to block pathological α-synuclein aggregation in synucleinopathies

The prion-like propagation and accumulation of pathogenic α-synuclein (α-syn) aggregates in the central nervous system are central drivers of Parkinson’s disease (PD) and related synucleinopathies, and remain an important therapeutic target. However, most reported anti-fibrillogenesis agents show limited efficacy in cells or in vivo, and their mechanisms are often poorly defined. Here, we report the unexpected finding that Pittsburgh compound B (PiB), the first clinically used amyloid tracer, selectively suppresses α-syn aggregation. Using an optimized PiB analog, HQY1027, we demonstrate that these compounds function as chemical chaperones. By directly binding polymorphic α-syn fibrils, they remodel the fibril surface and enhance Hsp40 recognition of fibril cores, thereby suppressing fibril formation both in vitro and in cells. HQY1027 is highly effective in neuronal models and significantly reduced α-syn aggregate propagation and motor deficits in a PD mouse model. Our findings establish a chemical chaperone strategy for targeting pathogenic α-syn and identify HQY1027 as a promising therapeutic lead for synucleinopathies. These results further highlight the potential of phenotype-based discovery and optimization of fibril-binding ligands to target intractable protein aggregates in neurodegenerative disorders.