α-Helical Motif as Inhibitors of Toxic Amyloid-β Oligomer Generation via Highly Specific Recognition of Amyloid Surface

• DOI: 10.1016/j.isci.2019.06.022
• Publication Date: 2019-06-18T04:05:39Z
• Authors: Yixiang Jiang; Xuehan Jiang; Xiaodong Shi; Fadeng Yang; Yang Cao; Xuan Qin; Zhanfeng Hou; Mingsheng Xie; Na Liu; Qi Fang; Feng Yin; Wei Han; Zigang Li
• Keywords: Oligomer; Amyloid (mycology); Rational design; Amyloid disease

Amyloid fibril surfaces can convert soluble proteins into toxic oligomers and are attractive targets for intervention of protein aggregation diseases. Thus far, molecules identified with inhibitory activity either large or flat cyclic compounds lacking in specificity. The main design difficulty is flatness amyloid the lack knowledge on binding interfaces. Here, we demonstrate, first time, a rational alpha-helical peptide inhibitors targeting amyloid-beta 40 (Aβ40) surfaces, based our silico finding that helical fragment Aβ40 interacts unique way side-chain arrays surface. We strengthen fragment's capability through mutations helicity enhancement Terminal Aspartic acid strategy. resulting inhibitor shows micromolar affinity surface, effectively impedes surface-mediated oligomerization Aβ40, mitigates its cytotoxicity. This work opens up an avenue to designing modulators