Mapping ApoE/Aβ binding regions to guide inhibitor discovery

作者：Liu, Qian; Wu, Wei-hui; Fang, Chuan-lin; Li, Ren-wang; Liu, Peng; Lei, Peng; Hu, Jia; Sun, Xun; Zheng, Yi-zhe; Zhao, Yu-fen; Li, Yan-mei^*

来源：Molecular Biosystems, 2011, 7(5): 1693-1700.

DOI：10.1039/c1mb05019b

• AMYLOID-BETA
• ALZHEIMERS-DISEASE
• APOLIPOPROTEIN-E
• A-BETA
• CONGO RED
• FIBRIL FORMATION
• MOUSE MODEL
• PEPTIDE
• DEPOSITION
• CLEARANCE

Blocking the interaction between the E4 isoform of apolipoprotein E (ApoE) and amyloid beta-peptide (A beta) may be an avenue for pharmacological intervention in Alzheimer's disease (AD). The main regions of interaction of the two proteins are, respectively, ApoE244-272 and A beta 12-28. These protein segments are too large to facilitate the design of small molecule inhibitors. We mapped the primary components of ApoE/A beta interaction to smaller peptide segments. Within the three motifs that are primarily responsible for ApoE/A beta interaction, we identified four peptides that substantially block ApoE/A beta interaction and further improved their inhibitory activity by rational hydrophobic amino acid substitution. Moreover, the mapping results provide the clue that the A beta residues which interact with ApoE appear to be in the same region where A beta self-interacts. According to this information, we found that Congo Red and X-34 could strongly inhibit ApoE/A beta interaction. Our findings extend our understanding of ApoE/A beta interaction and may guide the discovery of inhibitors that treat AD by antagonizing ApoE/A beta interaction.

• 出版日期2011
• 单位清华大学