Harnessing chaperones to generate small-molecule inhibitors of amyloid beta aggregation.
Gestwicki JE, Crabtree GR, Graef IA.
Department of Pathology, Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305, USA.
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.


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