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De Novo Design of Self-assembled Hexapeptides as Β-amyloid (Aβ) Peptide Inhibitors
ACS Chemical Neuroscience
  • Jie Zheng, University of Akron
  • Ge Zhang, University of Akron Main Campus
  • Mingzhen Zhang, University of Akron Main Campus
  • Qiuming Wang
  • Guizhao Liang
  • Mingzhen Zhang
  • Jun Zhao
  • Kunal Patel
  • Xiang Yu
  • Chao Zhao
  • Binrong Ding
  • Feimeng Zhou
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The ability of peptides to construct specific secondary structures provides a useful function for biomaterial design that cannot be achieved with traditional organic molecules and polymers. Inhibition of amyloid formation is a promising therapeutic approach for the treatment of neurodegenerative diseases. Existing peptide-based inhibitors are mainly derived from original amyloid sequences, which have very limited sequence diversity and activity. It is highly desirable to explore other peptide-based inhibitors that are not directly derived from amyloid sequences. Here, we develop a hybrid high-throughput computational method to efficiently screen and design hexapeptide inhibitors against amyloid-β (Aβ) aggregation and toxicity from the first principle. Computationally screened/designed inhibitors are then validated for their inhibition activity using biophysical experiments. We propose and demonstrate a proof-of-concept of the “like-interacts-like” design principle that the self-assembling peptides are able to interact strongly with conformationally similar motifs of Aβ peptides and to competitively reduce Aβ–Aβ interactions, thus preventing Aβ aggregation and Aβ-induced toxicity. Such a de novo design can also be generally applicable to design new peptide inhibitors against other amyloid diseases, beyond traditional peptide inhibitors with homologous sequences to parent amyloid peptides.
Citation Information
Jie Zheng, Ge Zhang, Mingzhen Zhang, Qiuming Wang, et al.. "De Novo Design of Self-assembled Hexapeptides as Β-amyloid (Aβ) Peptide Inhibitors" ACS Chemical Neuroscience Vol. 5 Iss. 10 (2014) p. 972 - 981
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