Specific aromatic foldamers potently inhibit spontaneous and seeded Aß42 and Aß43 fibril assembly.

Amyloid fibrils are self-propagating entities that spread pathology in several devastating disorders including Alzheimer's disease (AD). In AD, amyloid-ß (Aß) peptides form extracellular plaques that contribute to cognitive decline. One potential therapeutic strategy is to develop inhibitors that prevent Aß 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 Aß fibrillization. Ac-Sal-(Lys-Sal)3-CONH2 and Sal-(Lys-Sal)3-CONH2 selectively inhibited Aß42 fibrillization, but were ineffective against Aß43, an overlooked species that is highly neurotoxic and frequently deposited in AD brains. By contrast, (Arg-Benz)4-CONH2 and (Arg-Sal)3-(Cit-Sal)-CONH2 prevented spontaneous and seeded Aß42 and Aß43 fibrillization. Importantly, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibited formation of toxic Aß42 and Aß43 oligomers and proteotoxicity. None of these foldamers inhibited Sup35 prionogenesis, but Sal-(Lys-Sal)3-CONH2 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 Aß42 fibrillization do not necessarily inhibit Aß43 fibrillization. Moreover, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibits formation of toxic Aß conformers and seeding activity, properties that could have therapeutic utility.

Environment- and sequence-dependence of helical type in membrane-spanning peptides composed of ß3-amino acids.

Transmembrane (TM) ß-peptides comprised of acyclic ß(3)-amino acids demonstrate equilibrium between 12- and 14-helical structures in an environment- and sequence-dependent manner. Circular dichroism (CD) spectra of TM ß(3)-peptides may be described as linear combinations of the 12- and 14-helical CD spectra. The apparent malleability of ß(3)-substituted acyclic ß-peptides has practical implications for foldamer design, as it suggests that both the 14-helix and 12-helix might be reasonable platforms for molecular recognition.