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Front Mol Neurosci. 2019 Mar 4;12:54. doi: 10.3389/fnmol.2019.00054. eCollection 2019.

Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation.

Author information

1
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China.
2
UCLA-DOE Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, CA, United States.
3
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
4
University of Chinese Academy of Sciences, Beijing, China.
5
Shanghai Center for Women and Children's Health, Shanghai, China.
6
Department of Chemistry, University of California, Irvine, Irvine, CA, United States.
7
Department of Neurology, Easton Center for Alzheimer's Disease Research, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

Abstract

Many human neurodegenerative diseases are associated with amyloid fibril formation. Inhibition of amyloid formation is of importance for therapeutics of the related diseases. However, the development of selective potent amyloid inhibitors remains challenging. Here based on the structures of amyloid β (Aβ) fibrils and their amyloid-forming segments, we designed a series of peptide inhibitors using RosettaDesign. We further utilized a chemical scaffold to constrain the designed peptides into β-strand conformation, which significantly improves the potency of the inhibitors against Aβ aggregation and toxicity. Furthermore, we show that by targeting different Aβ segments, the designed peptide inhibitors can selectively recognize different species of Aβ. Our study developed an approach that combines the structure-based rational design with chemical modification for the development of amyloid inhibitors, which could be applied to the development of therapeutics for different amyloid-related diseases.

KEYWORDS:

Alzheimer’s disease; Aβ fibril; neurodegenerative diseases; protein misfolding; structure-based inhibitor design

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