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Keywords:

  • Alzheimer's disease;
  • neurodegeneration;
  • protein misfolding;
  • thioflavin T

Self-assembly of amyloid beta into fibrillar plaques is characteristic of Alzheimer’s disease and oligomers of this peptide are believed to be involved in neurodegeneration. Natural organic dyes, such as congo red and curcumin, bind tightly to amyloid beta and, at higher concentrations, block its self-assembly. The ability of these molecules to prevent amyloid accumulation has generated interest in understanding which of their structural features contribute to inhibitory potency. In general, amyloid beta ligands tend to be flat, planar molecules with substituted aromatic end groups; however, a comprehensive structure–activity study has not been reported. To better understand these ligands, we surveyed the effect of three prominent features on inhibition of amyloid aggregation: the presence of two aromatic end groups, the substitution pattern of these aromatics, and the length and flexibility of the linker region. We found that modification of any one of the modules has profound effects on activity. Further, we report that the optimal length of the linker lies within a surprisingly narrow regime (6–19 Å). These results offer insight into the key chemical features required for inhibiting amyloid beta aggregation. In turn, these findings help define the nature of the docking site for small molecules on the amyloid beta surface.