Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

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.

Chiral Linked Systems as a Model for Understanding D-Amino Acids Influence on the Structure and Properties of Amyloid Peptides

“…As mentioned in the introduction, the nature of neurodegenerative diseases, including Alzheimer’s disease, is largely related to amyloid Aβ42 [ 1 , 2 , 3 , 4 ]. At the same time, research of this amyloid is carried out in several directions, on the one hand, the toxicity of oligomers of this amyloid relative to brain cells is studied [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ], and on the other hand, its structure is explored [ 3 , 4 , 9 ]. One of the main questions: how does the structure of this peptide change when of L-amino acids are replaced by D-analog?…”

“…The choice of NSAIDs is not accidental, since the derivatives of these drugs are now being tested as inhibitor of γ-secretase-a complex of enzymes involved in the synthesis of Aβ42 from precursor of amyloid protein (APP) [18,19]. The mechanisms of the Aβ42 monomer action and its aggregated forms have been studied in cell models, while the primary cause of the formation of aggregates and their relationship with the inclusion of D-amino acids in biomolecules remains to be studied [3,4,[9][10][11]. This review describes first results on the influence of D-amino acids on the structure and properties, obtained in the study of model systems (Figure 1).…”

“…The mechanisms of the Aβ42 monomer action and its aggregated forms have been studied in cell models, while the primary cause of the formation of aggregates and their relationship with the inclusion of D-amino acids in biomolecules remains to be studied [ 3 , 4 , 9 , 10 , 11 ]. This review describes first results on the influence of D-amino acids on the structure and properties, obtained in the study of model systems ( Figure 1 ).…”

Hereditary Transthyretin-Related Amyloidosis: Genetic Heterogeneity and Early Personalized Gene Therapy

“…Reliable data exists, providing a clear picture of the epidemiology in several countries in the European Community. Over time, new diagnostic and therapeutic approaches were adopted, reducing misdiagnosis and contributing to the quality and life expectancy of the affected patients [ 10 , 11 , 12 , 13 ].…”

Understanding Amyloid Structures and Disease: A Continuing Challenge in Health Research

“…By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, Kim et al [ 7 ] found that a small series of diphenyl-methane-based thyroid hormone analogs, including well-characterized lipid lowering agent Sobetirome [ 8 ], originally named GC-1, and recently developed TRβ selective agonist IS25 and its prodrug TG68 [ 9 , 10 ] act as TTR stabilizers and efficient suppressors of TTR aggregation, further expanding the potential of thyromimetics as multi-functional therapeutic molecules for TTR-related pathologies, including NDDs.…”