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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

J Med Chem. 2020; 
Cotrina EY, Gimeno A, Llop J, Jiménez-Barbero J, , Quintana J, Valencia G, Cardoso I, Prohens R, Arsequell G.
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Peptide Synthesis Depsi-Aβ(1-42) peptide, a chemically-modified β-amyloid (1-42) precursor containing a isoacyl dipeptide at residues Gly-Ser, was available from GenScript (Ref.... The native Aβ(1-42) peptide was obtained from depsi-Aβ(1- 42) peptide (Genscript, RP10017-1, purity by HPLC > 96%), a chemically-modified β- ACS Paragon Plus Environment Page 21 of 39 Journal of Medicinal Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 amyloid (1-42) precursor, by a switching procedure involving a change in pH and immediate use. Get A Quote

摘要

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 ... More

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