Binding of Monovalent and Bivalent Ligands by Transthyretin Causes Different Short- and Long-Distance Conformational Changes

Corazza, Alessandra; Verona, Guglielmo; Waudby, Christopher A.; Mangione, Palma; Bingham, Ryan P.; Uings, Iain; Canetti, Diana; Nocerino, Paola; Taylor, Graham W.; Pepys, Mark B.; Christodoulou, John; Bellotti, Vittorio

doi:10.1021/acs.jmedchem.9b01037

Cited by 27 publications

(28 citation statements)

References 30 publications

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“…For example, tolcapone, the approved drug molecule for Parkinson’s disease, was shown to bind to TTR tetramer better than tafamidis and exhibit superior BBB permeability, thus being a strong therapeutic candidate for TTR amyloidosis [ 16 , 17 ]. In addition, the recent development of mds84, the bivalent binder occupying both T 4 binding pockets simultaneously, has attracted attention because it has shown highly potent effects not only for tetramer stabilization but also for the prevention of TTR proteolysis [ 18 ]; the proteolysis-induced fragmentation of TTR was recently proposed as an important mechanism facilitating TTR amyloidosis [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Runfola

Rapposelli

et al. 2021

IJMS

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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.

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Section: Introductionmentioning

confidence: 99%

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Runfola

Rapposelli

et al. 2021

IJMS

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“…Other rationally designed small molecule TTR tetramer binders, including the palindromic molecule mds84, which simultaneously occupies both T4-binding pockets of TTR tetramers ( Kolstoe et al., 2010 ; Corazza et al., 2019 ), are in preclinical development.…”

Section: Elimination or Reduction Of The Amyloid-forming Protein Tranmentioning

confidence: 99%

Treating Protein Misfolding Diseases: Therapeutic Successes Against Systemic Amyloidoses

Nevone

Merlini

2020

Front. Pharmacol.

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Misfolding and extracellular deposition of proteins is the hallmark of a heterogeneous group of conditions collectively termed protein misfolding and deposition diseases or amyloidoses. These include both localized (e.g. Alzheimer’s disease, prion diseases, type 2 diabetes mellitus) and systemic amyloidoses. Historically regarded as a group of maladies with limited, even inexistent, therapeutic options, some forms of systemic amyloidoses have recently witnessed a series of unparalleled therapeutic successes, positively impacting on their natural history and sometimes even on their incidence. In this review article we will revisit the most relevant of these accomplishments. Collectively, current evidence converges towards a crucial role of an early and conspicuous reduction or stabilization of the amyloid-forming protein in its native conformation. Such an approach can reduce disease incidence in at risk individuals, limit organ function deterioration, promote organ function recovery, improve quality of life and extend survival in diseased subjects. Therapeutic success achieved in these forms of systemic amyloidoses may guide the research on other protein misfolding and deposition diseases for which effective etiologic therapeutic options are still absent.

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“…Contrarily to the above-mentioned compounds, palindromic ligands, such as mds84, rapidly bind simultaneously to both T 4binding sites in each tetrameric TTR molecule, which would overcome the problems of negative cooperativity of the binding of the existing drugs, such as tafamidis. Mds84 binds to the native TTR wt in whole serum and, more effectively to the amyloidogenic TTR variants, promoting the stabilization of the TTR tetramer (Kolstoe et al, 2010;Corazza et al, 2019).…”

Section: Ttr Stabilizationmentioning

confidence: 99%

Modulation of the Mechanisms Driving Transthyretin Amyloidosis

Bezerra

Saraiva

Almeida

2020

Front. Mol. Neurosci.

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Transthyretin (TTR) amyloidoses are systemic diseases associated with TTR aggregation and extracellular deposition in tissues as amyloid. The most frequent and severe forms of the disease are hereditary and associated with amino acid substitutions in the protein due to single point mutations in the TTR gene (ATTRv amyloidosis). However, the wild type TTR (TTR wt) has an intrinsic amyloidogenic potential that, in particular altered physiologic conditions and aging, leads to TTR aggregation in people over 80 years old being responsible for the non-hereditary ATTRwt amyloidosis. In normal physiologic conditions TTR wt occurs as a tetramer of identical subunits forming a central hydrophobic channel where small molecules can bind as is the case of the natural ligand thyroxine (T4). However, the TTR amyloidogenic variants present decreased stability, and in particular conditions, dissociate into partially misfolded monomers that aggregate and polymerize as amyloid fibrils. Therefore, therapeutic strategies for these amyloidoses may target different steps in the disease process such as decrease of variant TTR (TTRv) in plasma, stabilization of TTR, inhibition of TTR aggregation and polymerization or disruption of the preformed fibrils. While strategies aiming decrease of the mutated TTR involve mainly genetic approaches, either by liver transplant or the more recent technologies using specific oligonucleotides or silencing RNA, the other steps of the amyloidogenic cascade might be impaired by pharmacologic compounds, namely, TTR stabilizers, inhibitors of aggregation and amyloid disruptors. Modulation of different steps involved in the mechanism of ATTR amyloidosis and compounds proposed as pharmacologic agents to treat TTR amyloidosis will be reviewed and discussed.

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Binding of Monovalent and Bivalent Ligands by Transthyretin Causes Different Short- and Long-Distance Conformational Changes

Cited by 27 publications

References 30 publications

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Treating Protein Misfolding Diseases: Therapeutic Successes Against Systemic Amyloidoses

Modulation of the Mechanisms Driving Transthyretin Amyloidosis

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