Cited 0 time in
Cited 3 time in
Diphenyl-methane based thyromimetic inhibitors for transthyretin amyloidosis
- Title
- Diphenyl-methane based thyromimetic inhibitors for transthyretin amyloidosis
- Authors
- Kim, Bokyung; Ko, Young Ho; Runfola, Massimiliano; Rapposelli, Simona; Ortore, Gabriella; Chiellini, Grazia; Kim, 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 aggregation; Sobetirome; Thyromimetics; Transthyretin; TTR amyloidosis; TTR 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
-
-
Kim, Jin Hae
Protein Structure Aging Laboratory
-
Research Interests
- Files:
-
- Collection:
- Department of New BiologyProtein Structure Aging Laboratory1. Journal Articles
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.