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Title: Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta

Abstract

Amyloid protein aggregates are associated with dozens of devastating diseases including Alzheimer’s, Parkinson’s, ALS, and diabetes type 2. While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease. Here we show that knowledge of the atomic structure of one of the adhesive, steric-zipper segments of the amyloid-beta (Aβ) protein of Alzheimer’s disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce Aβ cytotoxicity against mammalian cells by up to 90%. Although these compounds bind to Aβ fibers, they do not reduce fiber formation of Aβ. Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, UCLA–DOE Institute for Genomics and Proteomics, University of California, Los Angeles, Los Angeles, United States
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1197662
Alternate Identifier(s):
OSTI ID: 1197667
Grant/Contract Number:  
FC02-02ER63421
Resource Type:
Published Article
Journal Name:
eLife
Additional Journal Information:
Journal Name: eLife Journal Volume: 2; Journal ID: ISSN 2050-084X
Publisher:
eLife Sciences Publications, Ltd.
Country of Publication:
United States
Language:
English

Citation Formats

Jiang, Lin, Liu, Cong, Leibly, David, Landau, Meytal, Zhao, Minglei, Hughes, Michael P., and Eisenberg, David S. Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta. United States: N. p., 2013. Web. doi:10.7554/eLife.00857.
Jiang, Lin, Liu, Cong, Leibly, David, Landau, Meytal, Zhao, Minglei, Hughes, Michael P., & Eisenberg, David S. Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta. United States. doi:10.7554/eLife.00857.
Jiang, Lin, Liu, Cong, Leibly, David, Landau, Meytal, Zhao, Minglei, Hughes, Michael P., and Eisenberg, David S. Tue . "Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta". United States. doi:10.7554/eLife.00857.
@article{osti_1197662,
title = {Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta},
author = {Jiang, Lin and Liu, Cong and Leibly, David and Landau, Meytal and Zhao, Minglei and Hughes, Michael P. and Eisenberg, David S.},
abstractNote = {Amyloid protein aggregates are associated with dozens of devastating diseases including Alzheimer’s, Parkinson’s, ALS, and diabetes type 2. While structure-based discovery of compounds has been effective in combating numerous infectious and metabolic diseases, ignorance of amyloid structure has hindered similar approaches to amyloid disease. Here we show that knowledge of the atomic structure of one of the adhesive, steric-zipper segments of the amyloid-beta (Aβ) protein of Alzheimer’s disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce Aβ cytotoxicity against mammalian cells by up to 90%. Although these compounds bind to Aβ fibers, they do not reduce fiber formation of Aβ. Structure-activity relationship studies of the fiber-binding compounds and their derivatives suggest that compound binding increases fiber stability and decreases fiber toxicity, perhaps by shifting the equilibrium of Aβ from oligomers to fibers.},
doi = {10.7554/eLife.00857},
journal = {eLife},
number = ,
volume = 2,
place = {United States},
year = {2013},
month = {7}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.7554/eLife.00857

Citation Metrics:
Cited by: 52 works
Citation information provided by
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