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Calorimetric Studies of Binary and Ternary Molecular Interactions between Transthyretin, A? 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 (A?) 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?(1-42) peptide, and TTR stabilizers using isothermal titration calorimetry (ITC). A TTR/A?(1-42) (1:1) complex with a dissociation constant of Kd = 0.94 ?M is formed; with IDIF (4), this constant improves up to Kd = 0.32 ?M, indicating the presence of a ternary complex TTR/IDIF/A?(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?(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).

SUBMITTER: Cotrina EY

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

REPOSITORIES: biostudies-literature

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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.

Cotrina Ellen Y EY Gimeno Ana A Llop Jordi J Jiménez-Barbero Jesús J Quintana Jordi J Valencia Gregorio G Cardoso Isabel I Prohens Rafel R Arsequell Gemma G

Journal of medicinal chemistry 20200318 6

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 ...[more]

PMID: 32124607

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Project description:The main goal of this paper was to study the optical, electrical, and thermal properties of hybrid composites based on biodegradable polymers (L,D-poly(lactic acid), polycaprolactone or Ecoflex®), single walled carbon nanotubes (SWCN), and 4'-pentyl-4-biphenylcarbonitrile (5CB). The biodegradable polymers' binary and ternary compositions were analyzed in detail by ultraviolet and visible (UV-Vis) spectroscopy taking into consideration their chemical structure and interactions with 5CB and SWCN. Differential scanning calorimetry (DSC) studies of the created hybrid layers showed thermal stability and changes in glass transition temperature and melting point in comparison to neat polymers, depending on the chemical structure of the polymer used and the type of composition. Morphology of the created layers were investigated by atomic force and polarizing microscopy. The static contact angle measurements of a water drop showed that all of the neat polymer layers were hydrophobic with angle values ranging from 108° to 115°. In addition, in the case of the Ecoflex layers, both with and without additives, a rapid sorption of the deposited water drop was observed. Finally, a simple device with poly(ethylene terephthalate) (PET)/indium tin oxide (ITO)/poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS)/poly [[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6-diyl][3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4-b]thiophenediyl ]] (PTB7) : [6,6]-phenyl-C71-butyric acid methyl ester (PC70BM)/Ag/biodegradable polymer:SWCN architecture was constructed and tested using an infrared (IR) thermographic camera to investigate the surface defects on the created hybrid layers. Increasing the SWCN admixture from 0.01 to 0.5% significantly improved the conductivity only in the case of L,D-poly(lactic acid):SWCN (10:0.5), for which above 5 V, a current with a resistance of 3030.7 ? could be measured. In order to use the created layers as flexible electrodes, the first experiments were carried out with an admixture of SWCN and poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) as conductive compounds.

Project description:The demonstration of chaperone-like activity in peptides (mini-chaperones) derived from ?-crystallin's chaperone region has generated significant interest in exploring the therapeutic potential of peptide chaperones in diseases of protein aggregation. Recent studies in experimental animals show that mini-chaperones could reach intended targets and alter the disease phenotype. Although mini-chaperones show potential benefits against protein aggregation diseases, they do tend to form aggregates on storage. There is thus a need to fine-tune peptide chaperones to increase their solubility, pharmacokinetics, and biological efficacy.This review summarizes the properties and the potential therapeutic roles of mini-chaperones in protein aggregation diseases and highlights some of the refinements needed to increase the stability and biological efficacy of mini-chaperones while maintaining or enhancing their chaperone-like activity against precipitation of unfolding proteins.Mini-chaperones suppress the aggregation of proteins, block amyloid fibril formation, stabilize mutant proteins, sequester metal ions, and exhibit antiapoptotic properties. Much work must be done to fine-tune mini-chaperones and increase their stability and biological efficacy. Peptide chaperones could have a great therapeutic value in diseases associated with protein aggregation and apoptosis.Accumulation of misfolded proteins is a primary cause for many age-related diseases, including cataract, macular degeneration, and various neurological diseases. Stabilization of native proteins is a logical therapeutic approach for such diseases. Mini-chaperones, with their inherent antiaggregation and antiapoptotic properties, may represent an effective therapeutic molecule to prevent the cascade of protein conformational disorders. Future studies will further uncover the therapeutic potential of mini-chaperones. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.

Dataset Information

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

Publications

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.

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