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-CONH2 and Sal-(Lys-Sal)3-CONH2 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-CONH2 an