title: Specific aromatic foldamers potently inhibit spontaneous and seeded Aβ42 and Aβ43 fibril assembly.
abstract: 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 and (Arg-Sal)3-(Cit-Sal)-CONH2 prevented spontaneous and seeded Aβ42 and Aβ43 fibrillization. Importantly, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibited formation of toxic Aβ42 and Aβ43 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 Aβ42 fibrillization do not necessarily inhibit Aβ43 fibrillization. Moreover, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibits formation of toxic Aβ conformers and seeding activity, properties that could have therapeutic utility.
authors.affiliation: *Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
authors.forename: Katelyn M
authors.initials: KM
authors.lastname: Seither
authors.affiliation: *Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
authors.forename: Heather A
authors.initials: HA
authors.lastname: McMahon
authors.affiliation: *Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
authors.forename: Nikita
authors.initials: N
authors.lastname: Singh
authors.affiliation: *Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, U.S.A.
authors.forename: Hejia
authors.initials: H
authors.lastname: Wang
authors.forename: Mimi
authors.initials: M
authors.lastname: Cushman-Nick
authors.forename: Geronda L
authors.initials: GL
authors.lastname: Montalvo
authors.affiliation: ‡Department of Pharmaceutical Chemistry, University of California, San Francisco, CVRI-MC Box 3122, San Francisco, CA 94158-9001 U.S.A.
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.forename: James
authors.initials: J
authors.lastname: Shorter
mesh_terms: D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017510:Protein Folding / Q000187:drug effects
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D006841:Hydrocarbons, Aromatic; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C098994:amyloid beta-protein (1-43)