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-beta (A beta) peptides form extracellular plaques that contribute to cognitive decline. One potential therapeutic strategy is to develop inhibitors that prevent A beta 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 AP fibrillization. Ac-Sal-(Lys-Sal)(3)-CONH2 and Sal-(Lys-Sal)(3)-CONH2 selectively inhibited A beta 42 fibrillization, but were ineffective against A beta 43, an overlooked species that is highly neurotcodc and frequently deposited in AD brains. By contrast, (Arg-Benz)(4)-CONH2 and (Arg-Sal)(3)-(Cit-Sal)-CONH2 prevented spontaneous and seeded A beta 42 and A beta 43 fibrillization. Importantly, (Arg-Sal)(3)-(Cit-Sal)-CONH2 inhibited formation of toxic A beta 42 and A beta 43 oligomers and proteotoxicity. None of these foldamers inhibited Sup35 prionogenesis, but Sal-(Lys-Sal)(3)-CONH2 delayed aggregation of fused in sarcoma (PUS), an RNA-binding protein with a prion-like domain connected with amyotrophic lateral sclerosis and frontotemporal dementia. We establish that inhibitors of A beta 42 fibrillization do not necessarily inhibit A beta 43 fibrillization. Moreover, (Arg-Sal)(3)-(Cit-Sal)-CONH2 inhibits formation of toxic AP conformers and seeding activity, properties that could have therapeutic utility.