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Diphenyl-methane based thyromimetic inhibitors for transthyretin amyloidosis

Title
Diphenyl-methane based thyromimetic inhibitors for transthyretin amyloidosis
Authors
Kim, BokyungKo, Young HoRunfola, MassimilianoRapposelli, SimonaOrtore, GabriellaChiellini, GraziaKim, Jin Hae
DGIST Authors
Kim, Bokyung; Ko, Young Ho; Runfola, Massimiliano; Rapposelli, Simona; Ortore, Gabriella; Chiellini, Grazia; Kim, Jin Hae
Issue Date
2021-04
Citation
International Journal of Molecular Sciences, 22(7), 3488
Type
Article
Author Keywords
Protein aggregationSobetiromeThyromimeticsTransthyretinTTR amyloidosisTTR stabilizers
ISSN
1661-6596
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 thy-romimetics, 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 simula-tion, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thy-romimetics, 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
URI
http://hdl.handle.net/20.500.11750/13972
DOI
10.3390/ijms22073488
Publisher
Multidisciplinary Digital Publishing Institute (MDPI)
Related Researcher
Files:
Collection:
Department of New BiologyProtein Structure Aging Laboratory1. Journal Articles


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