Harnessing chaperones to generate small-molecule inhibitors of amyloid beta aggregation.
Protein aggregation is involved in the pathogenesis of neurodegenerative diseases and hence is considered an attractive target for therapeutic intervention. However, protein-protein interactions are exceedingly difficult to inhibit. Small molecules lack sufficient steric bulk to prevent interactions between large peptide surfaces. To yield potent inhibitors of beta-amyloid (Abeta) aggregation, we synthesized small molecules that increase their steric bulk by binding to chaperones but also have a moiety available for interaction with Abeta. This strategy yields potent inhibitors of Abeta aggregation and could lead to therapeutics for Alzheimer's disease and other forms of neurodegeneration.
Gestwicki
Jason E
JE
Department of Pathology, Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305, USA.
Crabtree
Gerald R
GR
Graef
Isabella A
IA
D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003224:Congo Red / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D003432:Cross-Linking Reagents; D005453:Fluorescence; D006624:Hippocampus / Q000166:cytology; D020287:In Situ Nick-End Labeling; D008024:Ligands; D008856:Microscopy, Fluorescence; D018832:Molecular Chaperones / Q000378:metabolism*; D015394:Molecular Structure; D016501:Neurites / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D022021:Tacrolimus Binding Proteins / Q000378:metabolism* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D008024:Ligands; D018832:Molecular Chaperones; D010446:Peptide Fragments; D010880:Piperidines; C493158:SLF-CR compound; C075222:amyloid beta-protein (1-42); D003224:Congo Red; D022021:Tacrolimus Binding Proteins