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.

ABSTRACT: 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 K_d = 0.94 μM is formed; with IDIF (4), this constant improves up to K_d = 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.

SUBMITTER: Cotrina EY 

PROVIDER: S-EPMC7115756 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature