Calorimetric Studies of Binary and Ternary Molecular Interactions between Transthyretin, Aβ Peptides, and Small-Molecule Chaperones toward an Alternative Strategy for Alzheimer's Disease Drug Discovery

Transthyretin (TTR) modulates the deposition, processing, and toxicity of Abeta (A beta) peptides. We have shown that this effect is enhanced in mice by treatment with small molecules such as iododiflunisal (IDIF, 4), a good TTR stabilizer. Here, we describe the thermodynamics of the formation of binary and ternary complexes among TTR, A beta(1-42) peptide, and TTR stabilizers using isothermal titration calorimetry (ITC). A TTR/A beta(1-42) (1:1) complex with a dissociation constant of K-d = 0.94 mu M is formed; with IDIF (4), this constant improves up to Kd = 0.32 mu M, indicating the presence of a ternary complex TTR/IDIF/A beta(1-42). However, with the drugs diflunisal (1) or Tafamidis (2), an analogous chaperoning effect could not be observed. Similar phenomena could be recorded with the shorter peptide A beta(12-28) (7). We propose the design of a simple assay system for the search of other chaperones that behave like IDIF and may become potential candidate drugs for Alzheimer's disease (AD).