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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 (A?) protein of Alzheimer's disease, when coupled with computational methods, identifies eight diverse but mainly flat compounds and three compound derivatives that reduce A? cytotoxicity against mammalian cells by up to 90%. Although these compounds bind to A? fibers, they do not reduce fiber formation of A?. 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 A? from oligomers to fibers. DOI:http://dx.doi.org/10.7554/eLife.00857.001.

SUBMITTER: Jiang L 

PROVIDER: S-EPMC3713518 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Jiang Lin L   Liu Cong C   Leibly David D   Landau Meytal M   Zhao Minglei M   Hughes Michael P MP   Eisenberg David S DS  

eLife 20130716


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,  ...[more]

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