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Publication Abstract from PubMed

Segments of proteins with high beta-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach to bind such segments in beta-strand and beta-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs bind their cognate peptides in vitro with nanomolar affinities. The crystal structure of a designed protein-peptide complex is close to the design model, and NMR characterization reveals how the peptide-binding cleft is protected in the apo state. We use the approach to design binders to the amyloid-forming proteins transthyretin, tau, serum amyloid A1 and amyloid beta(1-42) (Abeta42). The Abeta binders block the assembly of Abeta fibrils as effectively as the most potent of the clinically tested antibodies to date and protect cells from toxic Abeta42 species.

Design of amyloidogenic peptide traps.,Sahtoe DD, Andrzejewska EA, Han HL, Rennella E, Schneider MM, Meisl G, Ahlrichs M, Decarreau J, Nguyen H, Kang A, Levine P, Lamb M, Li X, Bera AK, Kay LE, Knowles TPJ, Baker D Nat Chem Biol. 2024 Aug;20(8):981-990. doi: 10.1038/s41589-024-01578-5. Epub 2024 , Mar 19. PMID:38503834^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.