Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta
Lin Jiang,
Cong Liu,
David Leibly,
Meytal Landau,
Minglei Zhao,
Michael P Hughes,
David S Eisenberg
Affiliations
Lin Jiang
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
Cong Liu
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
David Leibly
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
Meytal Landau
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
Minglei Zhao
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
Michael P Hughes
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
David S Eisenberg
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
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.
