Segments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach to bind such segments in β-strand and β-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 β₁₋₄₂ (Aβ42). The Aβ binders block the assembly of Aβ fibrils as effectively as the most potent of the clinically tested antibodies to date and protect cells from toxic Aβ42 species.

具有高β链倾向的蛋白质片段可以自我结合形成与许多疾病有关的淀粉样原纤维。我们描述了一种使用包含深层肽结合裂口的从头设计的支架将此类片段结合在 β 链和 β 发夹构象中的一般方法。该设计在体外以纳摩尔亲和力结合它们的同源肽。设计的蛋白质-肽复合物的晶体结构与设计模型接近，NMR 表征揭示了肽结合裂口如何在 apo 状态下受到保护。我们使用该方法设计淀粉样蛋白形成蛋白运甲状腺素蛋白、tau、血清淀粉样蛋白 A1 和淀粉样蛋白 β ₁₋₄₂ (Aβ42) 的结合剂。 Aβ 结合剂能够像迄今为止最有效的临床测试抗体一样有效地阻止 Aβ 原纤维的组装，并保护细胞免受有毒 Aβ42 物质的侵害。