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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

General rule of the essential interactions between BAFs and Aβ fiber can be derived from structure-based screening of Aβ toxicity inhibitor.The carbonyl group is used to represent the H-bond acceptor (or negative charge) of BAFs, and the naphthalene ring is used to represent the planar aromatic portion of BAFs. Based on the rounds of computing search and experimental test, the detailed description about essential interactions and geometrical parameters are in ‘Materials and methods’.DOI:http://dx.doi.org/10.7554/eLife.00857.030
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fig10: General rule of the essential interactions between BAFs and Aβ fiber can be derived from structure-based screening of Aβ toxicity inhibitor.The carbonyl group is used to represent the H-bond acceptor (or negative charge) of BAFs, and the naphthalene ring is used to represent the planar aromatic portion of BAFs. Based on the rounds of computing search and experimental test, the detailed description about essential interactions and geometrical parameters are in ‘Materials and methods’.DOI:http://dx.doi.org/10.7554/eLife.00857.030

Mentions: In the second cycle, nine new compounds were derived from the refined pharmacophore (Figure 7). Three of them detoxified Aβ in cell survival assay. BAF31, the best inhibitor which protected mammalian cells from Aβ toxicity in the second cycle, increased cell survival from the 40% induced by Aβ alone to >90% (Figure 3). A derivative of BAF31, BAF31ΔOH, lacking the hydroxyl group believed to bind to the Lys residue of the Aβ fiber (shown by the magenta oval in Figure 8B), is calculated no longer to bind to the Aβ fiber. NMR and cell viability assessments indicated that BAF31ΔOH binds much less strongly to Aβ fibers than BAF31 itself and shows significantly reduced power to inhibit toxicity (Figure 8E). Similarly, the detoxifying profile of derivatives of another inhibitor, BAF30, validated the key interactions of BAF30 across the binding interface (Figure 9). Our conclusion is that the NMR binding and toxicity results for the BAF derivatives studied are consistent with our model for the pharmacophore of Aβ (Figure 10).10.7554/eLife.00857.026Figure 7.New BAFs derived from the refined amyloid pharmacophore.


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)

General rule of the essential interactions between BAFs and Aβ fiber can be derived from structure-based screening of Aβ toxicity inhibitor.The carbonyl group is used to represent the H-bond acceptor (or negative charge) of BAFs, and the naphthalene ring is used to represent the planar aromatic portion of BAFs. Based on the rounds of computing search and experimental test, the detailed description about essential interactions and geometrical parameters are in ‘Materials and methods’.DOI:http://dx.doi.org/10.7554/eLife.00857.030
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig10: General rule of the essential interactions between BAFs and Aβ fiber can be derived from structure-based screening of Aβ toxicity inhibitor.The carbonyl group is used to represent the H-bond acceptor (or negative charge) of BAFs, and the naphthalene ring is used to represent the planar aromatic portion of BAFs. Based on the rounds of computing search and experimental test, the detailed description about essential interactions and geometrical parameters are in ‘Materials and methods’.DOI:http://dx.doi.org/10.7554/eLife.00857.030
Mentions: In the second cycle, nine new compounds were derived from the refined pharmacophore (Figure 7). Three of them detoxified Aβ in cell survival assay. BAF31, the best inhibitor which protected mammalian cells from Aβ toxicity in the second cycle, increased cell survival from the 40% induced by Aβ alone to >90% (Figure 3). A derivative of BAF31, BAF31ΔOH, lacking the hydroxyl group believed to bind to the Lys residue of the Aβ fiber (shown by the magenta oval in Figure 8B), is calculated no longer to bind to the Aβ fiber. NMR and cell viability assessments indicated that BAF31ΔOH binds much less strongly to Aβ fibers than BAF31 itself and shows significantly reduced power to inhibit toxicity (Figure 8E). Similarly, the detoxifying profile of derivatives of another inhibitor, BAF30, validated the key interactions of BAF30 across the binding interface (Figure 9). Our conclusion is that the NMR binding and toxicity results for the BAF derivatives studied are consistent with our model for the pharmacophore of Aβ (Figure 10).10.7554/eLife.00857.026Figure 7.New BAFs derived from the refined amyloid pharmacophore.

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