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.
Highlights
Transthyretin (TTR) is an essential transporter of the thyroid hormone (TH) and a holo-retinol-binding protein
The nuclear magnetic resonance (NMR) signal perturbation results were consistent with the X-ray crystallographic observations; the signals corresponding to the residues mentioned above either significantly broadened or shifted due to the addition of GC-1, IS25, or TG68
Other than knowing that TTR is the native transporter of TH, the potential effects of most thyromimetic molecules on TTR have not been studied in detail
Summary
Transthyretin (TTR) is an essential transporter of the thyroid hormone (TH) and a holo-retinol-binding protein. It was found that T4 binding to the hydrophobic pockets of TTR tetramer inhibited the acid-induced TTR aggregation; a set of thyromimetic molecules were designed as ‘kinetic stabilizers’ to repress monomer dissociation and fibril formation [11,12]. These efforts resulted in the development of tafamidis, a clinically proven drug for TTR amyloidosis [13]. Sci. 2021, 22, 3488 nism and to expand chemical diversity and functionality of GC-1 To this end, we first investigated whether the selected thyromimetics were able to suppress TTR amyloidosis.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
