De Novo Design of Self-Assembled Hexapeptides as 尾-Amyloid (A尾) Peptide Inhibitors
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- 作者：Qiuming Wang ; Guizhao Liang ; Mingzhen Zhang ; Jun Zhao ; Kunal Patel ; Xiang Yu ; Chao Zhao ; Binrong Ding ; Ge Zhang ; Feimeng Zhou ; Jie Zheng
- 刊名：ACS Chemical Neuroscience
- 出版年：2014
- 出版时间：October 15, 2014
- 年：2014
- 卷：5
- 期：10
- 页码：972-981
- 全文大小：533K
- ISSN：1948-7193
文摘
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-尾 (A尾) 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 鈥渓ike-interacts-like鈥?design principle that the self-assembling peptides are able to interact strongly with conformationally similar motifs of A尾 peptides and to competitively reduce A尾鈥揂尾 interactions, thus preventing A尾 aggregation and A尾-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.