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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Mol. Neurosci. | doi: 10.3389/fnmol.2019.00054

Structure-based peptide inhibitor design of amyloid- aggregation

 Jinxia Lu1,  Qin Cao2,  Chuchu Wang3, Jing Zheng4, Feng Luo3, Jingfei Xie3, Yichen Li1, Xiaojuan Ma3, Lin He1, 5, David Eisenberg2, James Nowick2,  Lin Jiang6* and  Dan Li1*
  • 1Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, China
  • 2UCLA-DOE Institute for Genomics and Proteomics, United States
  • 3Interdisciplinary Research Center on Biology and Chemistry, China
  • 4Shanghai Center for Women and Children's Health, China
  • 5Shanghai Center for Women and Children's Health, Shanghai 200062, China, Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, China
  • 6Department of Neurology, UCLA David Geffen School of Medicine, United States

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 and potent amyloid inhibitors remains challenging. Here based on the structures of A 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 A 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: Neurodegenerative Diseases, Alzheimer's disease, Aβ fibril, protein misfolding, Structure-based inhibitor design

Received: 12 Jan 2019; Accepted: 12 Feb 2019.

Edited by:

Jiajie Diao, University of Cincinnati, United States

Reviewed by:

Yanmei Li, Tsinghua University, China
Kailu Yang, Stanford University, United States
Ying Lai, Stanford University, United States  

Copyright: © 2019 Lu, Cao, Wang, Zheng, Luo, Xie, Li, Ma, He, Eisenberg, Nowick, Jiang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Lin Jiang, Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, 90095-1769, California, United States, jianglin@ucla.edu
Dr. Dan Li, Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, 200030, China, lidan2017@sjtu.edu.cn