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International Journal of Molecular Sciences
Article . 2021 . Peer-reviewed
License: CC BY
Data sources: Crossref
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PubMed Central
Other literature type . 2021
License: CC BY
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Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Authors: Bokyung Kim; Young Ho Ko; Massimiliano Runfola; Simona Rapposelli; Gabriella Ortore; Grazia Chiellini; Jin Hae Kim;

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Abstract

Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases.

Countries
Korea (Republic of), Italy
Keywords

MECHANISM, STABILIZATION, 570, Amyloid, Protein Folding, Thyroid Hormones, Magnetic Resonance Spectroscopy, Acetates, Molecular Dynamics Simulation, Transthyretin, FIBRIL FORMATION, transthyretin, Article, Permeability, protein aggregation, NATIVE-STATE, Phenols, Protein aggregation; Sobetirome; Thyromimetics; Transthyretin; TTR amyloidosis; TTR stabilizers; Acetates; Amyloid; Amyloid Neuropathies, Familial; Benzothiazoles; Biphenyl Compounds; Drug Design; Humans; Magnetic Resonance Spectroscopy; Methane; Molecular Docking Simulation; Molecular Dynamics Simulation; Permeability; Phenols; Prealbumin; Protein Binding; Protein Folding; Recombinant Proteins; Thyroid Hormones, TTR stabilizers, Humans, Prealbumin, Benzothiazoles, IODODIFLUNISAL, TTR amyloidosis, Amyloid Neuropathies, Familial, POTENT, DENATURATION, Biphenyl Compounds, Thyromimetics, thyromimetics, 540, Recombinant Proteins, sobetirome, Molecular Docking Simulation, INTERMEDIATE, Drug Design, Protein aggregation, LIGAND, Sobetirome, Methane, BETA PROTEIN, Protein Binding

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    popularity
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    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
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    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
7
Top 10%
Average
Top 10%
Green
gold