Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta
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 hind...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2013-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/00857 |
| _version_ | 1811201244276981760 |
|---|---|
| author | Lin Jiang Cong Liu David Leibly Meytal Landau Minglei Zhao Michael P Hughes David S Eisenberg |
| author_facet | Lin Jiang Cong Liu David Leibly Meytal Landau Minglei Zhao Michael P Hughes David S Eisenberg |
| author_sort | Lin Jiang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:17:56Z |
| format | Article |
| id | doaj.art-5a7cefc5de85489599727b82100f59f6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:17:56Z |
| publishDate | 2013-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-5a7cefc5de85489599727b82100f59f62022-12-22T03:52:12ZengeLife Sciences Publications LtdeLife2050-084X2013-07-01210.7554/eLife.00857Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid betaLin Jiang0Cong Liu1David Leibly2Meytal Landau3Minglei Zhao4Michael P Hughes5David S Eisenberg6Departments 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 StatesDepartments 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 StatesDepartments 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 StatesDepartments 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 StatesDepartments 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 StatesDepartments 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 StatesDepartments 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 StatesAmyloid 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.https://elifesciences.org/articles/00857amyloid fibercomputational biologydrug discoveryAlzheimer's diseaseligand docking |
| spellingShingle | Lin Jiang Cong Liu David Leibly Meytal Landau Minglei Zhao Michael P Hughes David S Eisenberg Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta eLife amyloid fiber computational biology drug discovery Alzheimer's disease ligand docking |
| title | Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta |
| title_full | Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta |
| title_fullStr | Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta |
| title_full_unstemmed | Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta |
| title_short | Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta |
| title_sort | structure based discovery of fiber binding compounds that reduce the cytotoxicity of amyloid beta |
| topic | amyloid fiber computational biology drug discovery Alzheimer's disease ligand docking |
| url | https://elifesciences.org/articles/00857 |
| work_keys_str_mv | AT linjiang structurebaseddiscoveryoffiberbindingcompoundsthatreducethecytotoxicityofamyloidbeta AT congliu structurebaseddiscoveryoffiberbindingcompoundsthatreducethecytotoxicityofamyloidbeta AT davidleibly structurebaseddiscoveryoffiberbindingcompoundsthatreducethecytotoxicityofamyloidbeta AT meytallandau structurebaseddiscoveryoffiberbindingcompoundsthatreducethecytotoxicityofamyloidbeta AT mingleizhao structurebaseddiscoveryoffiberbindingcompoundsthatreducethecytotoxicityofamyloidbeta AT michaelphughes structurebaseddiscoveryoffiberbindingcompoundsthatreducethecytotoxicityofamyloidbeta AT davidseisenberg structurebaseddiscoveryoffiberbindingcompoundsthatreducethecytotoxicityofamyloidbeta |