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 (Aβ) 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, Aβ(1–42)
peptide, and TTR stabilizers using isothermal titration calorimetry
(ITC). A TTR/Aβ(1–42) (1:1)
complex with a dissociation constant of Kd = 0.94 μM is formed; with IDIF
(4), this constant improves up to Kd = 0.32 μM, indicating
the presence of a ternary complex TTR/IDIF/Aβ(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 Aβ(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).