Potent inhibition of tau fibrillization with a multivalent ligand

• Published in: Biochemical and biophysical research communications Vol. 363; no. 1; pp. 229 - 234
• Main Authors: Honson, Nicolette S., Jensen, Jordan R., Darby, Michael V., Kuret, Jeff
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-11-2007
• Subjects: 60 APPLIED LIFE SCIENCES; AGGLOMERATION; Aggregation; Alzheimer’s disease; Amyloid - antagonists & inhibitors; Amyloid - ultrastructure; AQUEOUS SOLUTIONS; Binding Sites; Carbocyanines - chemistry; Cyanine dye; CYANINE DYES; DMSO; DRUGS; ELECTRON MICROSCOPY; INHIBITION; LIGANDS; LIQUID COLUMN CHROMATOGRAPHY; MASS SPECTROSCOPY; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - ultrastructure; NERVOUS SYSTEM DISEASES; Neurofibrillary tangle; Protein Binding; PROTEINS; SULFATES; SURFACTANTS; Tau; tau Proteins - antagonists & inhibitors; tau Proteins - ultrastructure; Aggregation; AD; Alzheimer’s disease; DMSO; MS; Hepes; LC; Tau; Neurofibrillary tangle; Cyanine dye; ODS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.08.166

Small-molecule inhibitors of tau fibrillization are under investigation as tools for interrogating the tau aggregation pathway and as potential therapeutic agents for Alzheimer’s disease. Established inhibitors include thiacarbocyanine dyes, which can inhibit recombinant tau fibrillization in the presence of anionic surfactant aggregation inducers. In an effort to increase inhibitory potency, a cyclic bis-thiacarbocyanine molecule containing two thiacarbocyanine moieties was synthesized and characterized with respect to tau fibrillization inhibitory activity by electron microscopy and ligand aggregation state by absorbance spectroscopy. Results showed that the inhibitory activity of the bis-thiacarbocyanine was qualitatively similar to a monomeric cyanine dye, but was more potent with 50% inhibition achieved at ∼80
nM concentration. At all concentrations tested in aqueous solution, the bis-thiacarbocyanine collapsed to form a closed clamshell structure. However, the presence of tau protein selectively stabilized the open conformation. These results suggest that the inhibitory activity of bis-thiacarbocyanine results from multivalency, and reveal a route to more potent tau aggregation inhibitors.