TY - JOUR TI - Structure-based discovery of fiber-binding compounds that reduce the cytotoxicity of amyloid beta AU - Jiang, Lin AU - Liu, Cong AU - Leibly, David AU - Landau, Meytal AU - Zhao, Minglei AU - Hughes, Michael P AU - Eisenberg, David S A2 - Kuriyan, John VL - 2 PY - 2013 DA - 2013/07/16 SP - e00857 C1 - eLife 2013;2:e00857 DO - 10.7554/eLife.00857 UR - https://doi.org/10.7554/eLife.00857 AB - 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. KW - amyloid fiber KW - computational biology KW - drug discovery KW - Alzheimer's disease KW - ligand docking JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -