Mapping ApoE/Aβ binding regions to guide inhibitor discovery

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

doi:10.1039/C1MB05019B

Mapping ApoE/Aβ binding regions to guide inhibitor discovery†

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

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* Corresponding authors

^a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing, P.R. China
E-mail: liym@mail.tsinghua.edu.cn
Fax: (+86)10-62781695
Tel: (+86)10-62796197

^b Institute of Chemical Defence, Beijing, P.R. China

Abstract

Blocking the interaction between the E4 isoform of apolipoprotein E (ApoE) and amyloid beta-peptide (Aβ) 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 Aβ12–28. These protein segments are too large to facilitate the design of small molecule inhibitors. We mapped the primary components of ApoE/Aβ interaction to smaller peptide segments. Within the three motifs that are primarily responsible for ApoE/Aβ interaction, we identified four peptides that substantially block ApoE/Aβ interaction and further improved their inhibitory activity by rational hydrophobic amino acid substitution. Moreover, the mapping results provide the clue that the Aβ residues which interact with ApoE appear to be in the same region where Aβ self-interacts. According to this information, we found that Congo Red and X-34 could strongly inhibit ApoE/Aβ interaction. Our findings extend our understanding of ApoE/Aβ interaction and may guide the discovery of inhibitors that treat AD by antagonizing ApoE/Aβ interaction.

Molecular BioSystems

Mapping ApoE/Aβ binding regions to guide inhibitor discovery†

Abstract

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Mapping ApoE/Aβ binding regions to guide inhibitor discovery

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