
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.
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
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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