期刊
ACS CHEMICAL NEUROSCIENCE
卷 5, 期 10, 页码 972-981出版社
AMER CHEMICAL SOC
DOI: 10.1021/cn500165s
关键词
Amyloid inhibitor; protein misfolding; self-assembled peptide; amyloid cytotoxicity; Alzheimer's disease
资金
- Natural Science Foundation Project of Chongqing CSTC [cstc2012gg-gjhz10003]
- NSF [CBET-0952624, CBET-1158447]
- Directorate For Engineering
- Div Of Chem, Bioeng, Env, & Transp Sys [0952624, 1158447] Funding Source: National Science Foundation
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-beta (A beta) 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 A beta peptides and to competitively reduce A beta-A beta interactions, thus preventing A beta aggregation and A beta-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.
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