Specific aromatic foldamers potently inhibit spontaneous and seeded Aβ42 and Aβ43 fibril assembly

Amyloid fibrils are self-propagating entities that spread pathology in several devastating disorders including Alzheimer's disease (AD). In AD, amyloid-β (Aβ) peptides form extracellular plaques that contribute to cognitive decline. One potential therapeutic strategy is to develop inhibitors that prevent Aβ misfolding into proteotoxic conformers. Here, we design specific aromatic foldamers, synthetic polymers with an aromatic salicylamide (Sal) or 3-amino benzoic acid (Benz) backbone, short length (four repetitive units), basic arginine (Arg), lysine (Lys) or citrulline (Cit) side chains, and various N- and C-terminal groups that prevent spontaneous and seeded Aβ fibrillization. Ac-Sal-(Lys-Sal)(3)-CONH(2) and Sal-(Lys-Sal)(3)-CONH(2) selectively inhibited Aβ42 fibrillization, but were ineffective against Aβ43, an overlooked species that is highly neurotoxic and frequently deposited in AD brains. By contrast, (Arg-Benz)(4)-CONH(2) and (Arg-Sal)(3)-(Cit-Sal)-CONH(2) prevented spontaneous and seeded Aβ42 and Aβ43 fibrillization. Importantly, (Arg-Sal)(3)-(Cit-Sal)-CONH(2) inhibited formation of toxic Aβ42 and Aβ43 oligomers and proteotoxicity. None of these foldamers inhibited Sup35 prionogenesis, but Sal-(Lys-Sal)(3)-CONH(2) delayed aggregation of fused in sarcoma (FUS), an RNA-binding protein with a prion-like domain connected with amyotrophic lateral sclerosis and frontotemporal dementia. We establish that inhibitors of Aβ42 fibrillization do not necessarily inhibit Aβ43 fibrillization. Moreover, (Arg-Sal)(3)-(Cit-Sal)-CONH(2) inhibits formation of toxic Aβ conformers and seeding activity, properties that could have therapeutic utility.