Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Autor: Massimiliano Runfola, Gabriella Maria Pia Ortore, Jin Hae Kim, Young Ho Ko, Grazia Chiellini, Simona Rapposelli, Bokyung Kim
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Protein Folding
Magnetic Resonance Spectroscopy
Acetates
Protein aggregation
Amyloid Neuropathies
lcsh:Chemistry
Familial
Prealbumin
Sobetirome
lcsh:QH301-705.5
Spectroscopy
biology
Chemistry
Amyloidosis
General Medicine
Recombinant Proteins
Computer Science Applications
Transport protein
sobetirome
Molecular Docking Simulation
Biochemistry
Methane
Protein Binding
Amyloid
Thyroid Hormones
endocrine system
Molecular Dynamics Simulation
Article
Permeability
Catalysis
transthyretin
protein aggregation
Inorganic Chemistry
Phenols
Tetramer
Thyromimetics
Transthyretin
TTR amyloidosis
TTR stabilizers
Amyloid Neuropathies
Familial
Benzothiazoles
Biphenyl Compounds
Drug Design
Humans
medicine
Physical and Theoretical Chemistry
Molecular Biology
Organic Chemistry
thyromimetics
nutritional and metabolic diseases
medicine.disease
Amyloid fibril
lcsh:Biology (General)
lcsh:QD1-999
Thyroid hormones
biology.protein
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 3488, p 3488 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 7
ISSN: 1661-6596
1422-0067
Popis: 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.
Databáze: OpenAIRE
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