title: De novo design of self-assembled hexapeptides as β-amyloid (Aβ) peptide inhibitors.
abstract: 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.
authors.affiliation: Department of Chemical and Biomolecular Engineering and ‡Department of Biomedical Engineering, The University of Akron , Akron, Ohio 44325, United States.
authors.forename: Qiuming
authors.initials: Q
authors.lastname: Wang
authors.forename: Guizhao
authors.initials: G
authors.lastname: Liang
authors.forename: Mingzhen
authors.initials: M
authors.lastname: Zhang
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Kunal
authors.initials: K
authors.lastname: Patel
authors.forename: Xiang
authors.initials: X
authors.lastname: Yu
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.forename: Binrong
authors.initials: B
authors.lastname: Ding
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D015195:Drug Design; D005453:Fluorescence; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D018625:Microscopy, Atomic Force; D056004:Molecular Dynamics Simulation; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D020349:Surface Plasmon Resonance; D013844:Thiazoles
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D018696:Neuroprotective Agents; D009842:Oligopeptides; D013844:Thiazoles; C009462:thioflavin T
keywords: Alzheimer’s disease; Amyloid inhibitor; amyloid cytotoxicity; protein misfolding; self-assembled peptide