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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 peak assignment of BAF1 with Aβ16–21 fiber.The 1D 1H NMR spectrum shows the aromatic proton regions of BAF1 upon the titration of Aβ16–21 fibers shown in Figure 5A. The insert is the chemical structure of BAF1 with the color-labeled aromatic proton observed in the NMR spectrum. The arrows with different colors indicate the proton assignment for NMR peaks.DOI:http://dx.doi.org/10.7554/eLife.00857.019
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fig5s1: NMR peak assignment of BAF1 with Aβ16–21 fiber.The 1D 1H NMR spectrum shows the aromatic proton regions of BAF1 upon the titration of Aβ16–21 fibers shown in Figure 5A. The insert is the chemical structure of BAF1 with the color-labeled aromatic proton observed in the NMR spectrum. The arrows with different colors indicate the proton assignment for NMR peaks.DOI:http://dx.doi.org/10.7554/eLife.00857.019

Mentions: (A) Atomic model of BAF11 from the initial cycle docked on the full-length Aβ fiber, viewed in perpendicular to the fiber axis (left panel) and down the fiber axis (right panel). BAF11 is shown as a cyan stick model, whose polar groups form hydrogen bonds (green thick lines) to Lys16 of Aβ. The extensive non-polar interactions arise from the flat aromatic rings of BAF11 packing against the hydrophobic surface formed by Val18 and Phe20 of Aβ. (B) Schematic representation of the polar and nonpolar interactions of BAF11 and its derivatives modeled on the Aβ fiber (in orange and light brown). In the process of the Aβ pharmacophore refinement, five different classes (I–V) of BAF11 derivatives were introduced into the second cycle of screening, to expand the BAF set and to assess the specificity of the compounds identified in the initial cycle. The full description and chemical structure of each derivative are in Table 3 and Figure 5—figure supplement 1. (C) Comparison of the toxicity inhibition (defined in ‘Materials and methods’) among five types of BAF11 derivatives after 24 hr incubation with Aβ (0.5 µM). Notice that all changes to BAF11 which remove binding groups diminish its effectiveness as an inhibitor of toxicity.


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 peak assignment of BAF1 with Aβ16–21 fiber.The 1D 1H NMR spectrum shows the aromatic proton regions of BAF1 upon the titration of Aβ16–21 fibers shown in Figure 5A. The insert is the chemical structure of BAF1 with the color-labeled aromatic proton observed in the NMR spectrum. The arrows with different colors indicate the proton assignment for NMR peaks.DOI:http://dx.doi.org/10.7554/eLife.00857.019
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig5s1: NMR peak assignment of BAF1 with Aβ16–21 fiber.The 1D 1H NMR spectrum shows the aromatic proton regions of BAF1 upon the titration of Aβ16–21 fibers shown in Figure 5A. The insert is the chemical structure of BAF1 with the color-labeled aromatic proton observed in the NMR spectrum. The arrows with different colors indicate the proton assignment for NMR peaks.DOI:http://dx.doi.org/10.7554/eLife.00857.019
Mentions: (A) Atomic model of BAF11 from the initial cycle docked on the full-length Aβ fiber, viewed in perpendicular to the fiber axis (left panel) and down the fiber axis (right panel). BAF11 is shown as a cyan stick model, whose polar groups form hydrogen bonds (green thick lines) to Lys16 of Aβ. The extensive non-polar interactions arise from the flat aromatic rings of BAF11 packing against the hydrophobic surface formed by Val18 and Phe20 of Aβ. (B) Schematic representation of the polar and nonpolar interactions of BAF11 and its derivatives modeled on the Aβ fiber (in orange and light brown). In the process of the Aβ pharmacophore refinement, five different classes (I–V) of BAF11 derivatives were introduced into the second cycle of screening, to expand the BAF set and to assess the specificity of the compounds identified in the initial cycle. The full description and chemical structure of each derivative are in Table 3 and Figure 5—figure supplement 1. (C) Comparison of the toxicity inhibition (defined in ‘Materials and methods’) among five types of BAF11 derivatives after 24 hr incubation with Aβ (0.5 µM). Notice that all changes to BAF11 which remove binding groups diminish its effectiveness as an inhibitor of toxicity.

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