Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK.
Department of Chemistry, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Sci Rep. 2020 Sep 17;10(1):15280. doi: 10.1038/s41598-020-69626-3.
Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31-42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer's disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.
双环肽具有巨大的治疗潜力，因为它们可以通过将大约 2 kDa 的低分子量与抗体样结合特异性相结合，在小分子和抗体之间架起桥梁。在这里，我们应用最近开发的计算合理设计策略来产生一种双环肽，以针对淀粉样β肽（Aβ42）的 42 个残基形式的 C 末端区域（残基 31-42），该蛋白质片段的聚集到淀粉样斑块与阿尔茨海默病有关。我们表明，这种双环肽能够在体外重塑 Aβ42 的聚集过程，并在表达 Aβ42 的秀丽隐杆线虫模型中降低其相关毒性。这些结果提供了一种计算方法设计针对无规蛋白特定表位的双环肽的初步示例。
