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

Jiang L, Liu C, Leibly D, Landau M, Zhao M, Hughes MP, Eisenberg DS - Elife (2013)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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. DOI:http://dx.doi.org/10.7554/eLife.00857.001.

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Related in: MedlinePlus

NMR titration of BAF8 with Aβ16–21 fibers.To validate our computation methods, NMR titration experiments were performed. (A) One representative peak of aromatic protons of the 1D 1H NMR spectra of the compound BAF8 (at 100µM) upon Aβ16–21 fibers titration (0–500 µM, monomer equivalent). (B) Fitting curve upon the area decrease of BAF8 NMR peaks as a function of fiber concentration. The apparent Kd of BAF8 (24 ± 5 µM) is lower than that of orange-G (Figure 4B), indicating the tighter binding affinity of BAF8 to Aβ16–21 fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.021
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fig5s3: NMR titration of BAF8 with Aβ16–21 fibers.To validate our computation methods, NMR titration experiments were performed. (A) One representative peak of aromatic protons of the 1D 1H NMR spectra of the compound BAF8 (at 100µM) upon Aβ16–21 fibers titration (0–500 µM, monomer equivalent). (B) Fitting curve upon the area decrease of BAF8 NMR peaks as a function of fiber concentration. The apparent Kd of BAF8 (24 ± 5 µM) is lower than that of orange-G (Figure 4B), indicating the tighter binding affinity of BAF8 to Aβ16–21 fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.021


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

Jiang L, Liu C, Leibly D, Landau M, Zhao M, Hughes MP, Eisenberg DS - Elife (2013)

NMR titration of BAF8 with Aβ16–21 fibers.To validate our computation methods, NMR titration experiments were performed. (A) One representative peak of aromatic protons of the 1D 1H NMR spectra of the compound BAF8 (at 100µM) upon Aβ16–21 fibers titration (0–500 µM, monomer equivalent). (B) Fitting curve upon the area decrease of BAF8 NMR peaks as a function of fiber concentration. The apparent Kd of BAF8 (24 ± 5 µM) is lower than that of orange-G (Figure 4B), indicating the tighter binding affinity of BAF8 to Aβ16–21 fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.021
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3713518&req=5

fig5s3: NMR titration of BAF8 with Aβ16–21 fibers.To validate our computation methods, NMR titration experiments were performed. (A) One representative peak of aromatic protons of the 1D 1H NMR spectra of the compound BAF8 (at 100µM) upon Aβ16–21 fibers titration (0–500 µM, monomer equivalent). (B) Fitting curve upon the area decrease of BAF8 NMR peaks as a function of fiber concentration. The apparent Kd of BAF8 (24 ± 5 µM) is lower than that of orange-G (Figure 4B), indicating the tighter binding affinity of BAF8 to Aβ16–21 fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.021
Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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. DOI:http://dx.doi.org/10.7554/eLife.00857.001.

Show MeSH
Related in: MedlinePlus