Ikenoue Tatsuya, Aprile Francesco A, Sormanni Pietro, Vendruscolo Michele
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, United Kingdom.
Front Neurosci. 2021 Feb 25;15:623097. doi: 10.3389/fnins.2021.623097. eCollection 2021.
There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid β peptide (Aβ42), since this molecular process is closely associated with Alzheimer's disease. The use of bicyclic peptides may offer novel opportunities for the effective modification of Aβ42 aggregation and the inhibition of its cytotoxicity, as these compounds combine the molecular recognition ability of antibodies with a relatively small size of about 2 kD. Here, to pursue this approach, we rationally designed a panel of six bicyclic peptides targeting various epitopes along the sequence of Aβ42 to scan its most amyloidogenic region (residues 13-42). Our kinetic analysis and structural studies revealed that at sub-stoichiometric concentrations the designed bicyclic peptides induce a delay in the condensation of Aβ42 and the subsequent transition to a fibrillar state, while at higher concentrations they inhibit such transition. We thus suggest that designed bicyclic peptides can be employed to inhibit amyloid formation by redirecting the aggregation process toward amorphous assemblies.
针对淀粉样β肽（Aβ42）42个氨基酸形式的聚集开展的药物研发项目备受关注，因为这一分子过程与阿尔茨海默病密切相关。双环肽的应用可能为有效改变Aβ42聚集及抑制其细胞毒性提供新机遇，因为这些化合物兼具抗体的分子识别能力，且尺寸相对较小，约为2 kD。在此，为探索该方法，我们合理设计了一组六种双环肽，靶向Aβ42序列上的不同表位，以扫描其最易形成淀粉样蛋白的区域（第13 - 42位氨基酸）。我们的动力学分析和结构研究表明，在亚化学计量浓度下，设计的双环肽会延迟Aβ42的凝聚以及随后向纤维状状态的转变，而在较高浓度下它们会抑制这种转变。因此，我们认为设计的双环肽可用于通过将聚集过程导向无定形聚集体来抑制淀粉样蛋白的形成。
