title: Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology.
abstract: An attractive strategy to treat proteinopathies (diseases caused by malformed or misfolded proteins) is to restore protein function by inducing proper three-dimensional structure. We hypothesized that this approach would be effective in reversing the detrimental effects of apolipoprotein (apo) E4, the major allele that significantly increases the risk of developing Alzheimer's disease and other neurodegenerative disorders. ApoE4's detrimental effects result from its altered protein conformation ("domain interaction"), making it highly susceptible to proteolytic cleavage and the generation of neurotoxic fragments. Here, we review apoE structure and function and how apoE4 causes neurotoxicity, and describe the identification of potent small-molecule-based "structure correctors" that induce proper apoE4 folding. SAR studies identified a series of small molecules that significantly reduced apoE4's neurotoxic effects in cultured neurons and a series that reduced apoE4 fragment levels in vivo, providing proof-of-concept for our approach. Structure-corrector-based therapies could prove to be highly effective for the treatment of many protein-misfolding diseases.
authors.affiliation: Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, California 94158, United States. rmahley@gladstone.ucsf.edu
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mahley
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001930:Brain Injuries / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding / Q000187:drug effects*; D021381:Protein Transport; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D053327:Apolipoprotein E4