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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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NMR titration of BAF31 and its derivative with the Aβ1–42 fiber.(A). 1D 1H NMR spectrum of BAF31 (100 µM) without (in black) and with Aβ1–42 fiber (12.5 µM monomer equivalent, in a green color). The magnified peaks are shown in the right panel to highlight the peak differences. (B). NMR spectrum of its derivative BAF31ΔOH (100 µM) when BAF31 is modified by the removal of a key hydroxyl group, without or with Aβ1–42 fiber (0 µM, 12.5 µM). The significant difference in NMR signal reduction between the BAF31 and BAF31ΔOH further validates the model of BAF31docked onto Aβ fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.028
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fig8s1: NMR titration of BAF31 and its derivative with the Aβ1–42 fiber.(A). 1D 1H NMR spectrum of BAF31 (100 µM) without (in black) and with Aβ1–42 fiber (12.5 µM monomer equivalent, in a green color). The magnified peaks are shown in the right panel to highlight the peak differences. (B). NMR spectrum of its derivative BAF31ΔOH (100 µM) when BAF31 is modified by the removal of a key hydroxyl group, without or with Aβ1–42 fiber (0 µM, 12.5 µM). The significant difference in NMR signal reduction between the BAF31 and BAF31ΔOH further validates the model of BAF31docked onto Aβ fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.028

Mentions: (A) Atomic model of the new inhibitor BAF31 (our most tightly binding BAF) derived from the refined pharmacophore (Figure 7, Figure 1F) in the second cycle, viewed perpendicular to the fiber axis on the left and down the fiber axis on the right. In panel (B), one important hydroxyl group forming hydrogen bonds to Lys16 residue of Aβ is highlighted by a magenta circle. (C) A representative NMR band (left panel) of mixture of Aβ fiber with the compound BAF31 compares with that (right panel) of Aβ fiber the derivative BAF31ΔOH which omits that important hydroxyl group. Their full NMR spectrums showing the same trend are shown in Figure 8—figure supplement 1. (D) Cell survival rates after 24 hr incubation with Aβ (0.5 µM), the molar ratio (1:5) of Aβ and the compound is comparable with the ratio in NMR binding experiment (C). (E) Notably, the elimination of one hydrogen bond from BAF31 (the derivative BAF31ΔOH) causes both the marked decrease in inhibition of Aβ toxicity to HeLa cells (D) and the loss of NMR binding to Aβ fibers (C).


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 BAF31 and its derivative with the Aβ1–42 fiber.(A). 1D 1H NMR spectrum of BAF31 (100 µM) without (in black) and with Aβ1–42 fiber (12.5 µM monomer equivalent, in a green color). The magnified peaks are shown in the right panel to highlight the peak differences. (B). NMR spectrum of its derivative BAF31ΔOH (100 µM) when BAF31 is modified by the removal of a key hydroxyl group, without or with Aβ1–42 fiber (0 µM, 12.5 µM). The significant difference in NMR signal reduction between the BAF31 and BAF31ΔOH further validates the model of BAF31docked onto Aβ fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.028
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig8s1: NMR titration of BAF31 and its derivative with the Aβ1–42 fiber.(A). 1D 1H NMR spectrum of BAF31 (100 µM) without (in black) and with Aβ1–42 fiber (12.5 µM monomer equivalent, in a green color). The magnified peaks are shown in the right panel to highlight the peak differences. (B). NMR spectrum of its derivative BAF31ΔOH (100 µM) when BAF31 is modified by the removal of a key hydroxyl group, without or with Aβ1–42 fiber (0 µM, 12.5 µM). The significant difference in NMR signal reduction between the BAF31 and BAF31ΔOH further validates the model of BAF31docked onto Aβ fibers.DOI:http://dx.doi.org/10.7554/eLife.00857.028
Mentions: (A) Atomic model of the new inhibitor BAF31 (our most tightly binding BAF) derived from the refined pharmacophore (Figure 7, Figure 1F) in the second cycle, viewed perpendicular to the fiber axis on the left and down the fiber axis on the right. In panel (B), one important hydroxyl group forming hydrogen bonds to Lys16 residue of Aβ is highlighted by a magenta circle. (C) A representative NMR band (left panel) of mixture of Aβ fiber with the compound BAF31 compares with that (right panel) of Aβ fiber the derivative BAF31ΔOH which omits that important hydroxyl group. Their full NMR spectrums showing the same trend are shown in Figure 8—figure supplement 1. (D) Cell survival rates after 24 hr incubation with Aβ (0.5 µM), the molar ratio (1:5) of Aβ and the compound is comparable with the ratio in NMR binding experiment (C). (E) Notably, the elimination of one hydrogen bond from BAF31 (the derivative BAF31ΔOH) causes both the marked decrease in inhibition of Aβ toxicity to HeLa cells (D) and the loss of NMR binding to Aβ fibers (C).

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