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16.04.2020Publication of the article "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."
PhD. Rafael Prohens, head of the Polymorphism and Calorimetry Technology of the CCiTUB has published the article "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" in the Journal of Medicinal Chemistry.
The summary of the article is:
"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)."
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