Design, synthesis, and properties of a chemically-tethered amyloid-β segment trimer resistant to inter-trimer mis-aggregation
Design, synthesis, and properties of a chemically-tethered amyloid-β segment trimer resistant to inter-trimer mis-aggregation
复制标题
抗三聚体间错误聚集的化学束缚淀粉样蛋白-β片段三聚体的设计、合成和特性
DOI：
10.1021/acs.joc.9b02612
复制
发表时间：
2020
期刊：
影响因子：
3.6
通讯作者：
Y. Sohma
中科院分区：
文献类型：
--
作者：
K. Shinoda;M. Kanai;Y. Sohma
淀粉样β肽（Aβ）寡聚体可能与阿尔茨海默病的发生发展有关。分离Aβ的特定寡聚体种类（即，二聚体、三聚体、四聚体等），然而，由于低聚物的瞬时的、不稳定的性质，这是困难的。在此，我们通过在与Aβ链共价连接的环肽系链中引入带电结构，提高了化学系链的Aβ25- 35三聚体对三聚体间错误聚集的抗性。化学栓系的三聚体的抗聚集性与栓系处的负电荷数正相关。因此，在系链处具有三个丙二酸的化学三聚体表现出高电阻，这是因为通过阴离子排斥减弱的自缔合。此外，丙二酸三聚体具有淀粉样蛋白生成特性，如交叉β-折叠结构、接种活性和细胞毒性。这是第一项证明非A β组分的化学修饰增强了化学连接的Aβ寡聚体的抗聚集性，从而维持了Aβ的结构完整性。三聚体间抗聚集三聚体的生物学/生物物理学评价可能为Aβ寡聚体的病理功能提供新的有用见解。
The oligomer species of amyloid-β peptide (Aβ) may be relevant to the development of Alzheimer’s disease. Isolating specific oligomer species of Aβ (i.e., dimers, trimers, tetramers, etc.), however, is difficult due to the transient, labile property of the oligomers. Here, we improved the resistance to intertrimer mis-aggregation of chemically tethered Aβ25–35trimers by introducing charged structures to the cyclic peptide tether that is covalently attached to the Aβ chain. The resistance to aggregation of the chemically tethered trimers positively correlated with the number of negative charges at the tether. Thus, a chemical trimer possessing three malonic acids at the tether exhibited high resistance because of the attenuated self-association by anionic repulsion. In addition, the malonic acid trimer possessed amyloidogenic properties such as cross-β-sheet structures, seeding activity, and cytotoxicity. This is the first study demonstrating that chemical modifications at the non-Aβ component enhance the resistance to aggregation of chemically tethered Aβ oligomers, by which the structural integrity of Aβ is maintained. Biological/biophysical evaluations of the intertrimer aggregation-resistant trimer may offer new, useful insights into the pathological functions of Aβ oligomers.