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The FEBS Journal Nov 2023Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small...
Transthyretin (TTR) is a carrier protein for thyroid hormone thyroxine (T ) in plasma, placental cytosol, and cerebrospinal fluid. While the potential toxicity of small molecules that compete with T for binding to TTR should be carefully studied, these small molecules can also serve as anti-ATTR amyloidosis drugs by stabilizing the TTR structure. Here, we demonstrated that rafoxanide, an EU-approved anthelmintic drug for domesticated animals, binds to the T -binding site of TTR. An intrinsic fluorescence quenching assay showed that rafoxanide also binds to the thyroid hormone-related proteins, including serum albumin and thyroid hormone receptor β. Rafoxanide strongly inhibited TTR amyloidogenesis in fibrillization assay, but the binding of rafoxanide to TTR was interfered with in human plasma, probably due to interactions with thyroid hormone-related proteins. Protein crystallography provided clues for the optimization of binding affinity and selectivity. Our findings emphasize the importance of considering rafoxanide as both a possible thyroid-disrupting chemical and a lead compound for the development of new ATTR amyloidosis inhibitors.
Topics: Animals; Humans; Female; Pregnancy; Prealbumin; Rafoxanide; Placenta; Thyroid Hormones; Amyloidosis; Anthelmintics; Anti-Infective Agents
PubMed: 37522420
DOI: 10.1111/febs.16915 -
Nature Reviews. Drug Discovery Nov 2015The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the... (Review)
Review
The aggregation of specific proteins is hypothesized to underlie several degenerative diseases, which are collectively known as amyloid disorders. However, the mechanistic connection between the process of protein aggregation and tissue degeneration is not yet fully understood. Here, we review current and emerging strategies to ameliorate aggregation-associated degenerative disorders, with a focus on disease-modifying strategies that prevent the formation of and/or eliminate protein aggregates. Persuasive pharmacological and genetic evidence now supports protein aggregation as the cause of postmitotic tissue dysfunction or loss. However, a more detailed understanding of the factors that trigger and sustain aggregate formation and of the structure-activity relationships underlying proteotoxicity is needed to develop future disease-modifying therapies.
Topics: Animals; Biological Factors; Humans; Neurodegenerative Diseases; Prealbumin; Protein Aggregation, Pathological; Protein Folding; Protein Transport; Structure-Activity Relationship; Treatment Outcome
PubMed: 26338154
DOI: 10.1038/nrd4593 -
European Journal of Heart Failure Sep 2022
Topics: Amyloid Neuropathies, Familial; Anticoagulants; Heart Failure; Humans; Prealbumin
PubMed: 35919942
DOI: 10.1002/ejhf.2648 -
Neurotherapeutics : the Journal of the... Oct 2021The past few years have witnessed an unprecedented acceleration in the clinical development of novel therapeutic options for hereditary transthyretin amyloidosis.... (Review)
Review
The past few years have witnessed an unprecedented acceleration in the clinical development of novel therapeutic options for hereditary transthyretin amyloidosis. Recently approved agents and drugs currently under investigation not only represent a major breakthrough in this field but also provide validation of the therapeutic potential of innovative approaches, like RNA interference and CRISPR-Cas9-mediated gene editing, in rare inherited disorders. In this review, we describe the evolving therapeutic landscape for hereditary transthyretin amyloidosis and discuss how this highly disabling and fatal condition is turning into a treatable disease. We also provide an overview of the molecular mechanisms involved in transthyretin (TTR) amyloid formation and regression, to highlight how a deeper understanding of these processes has contributed to the identification of novel treatment targets. Finally, we focus on major areas of uncertainty and unmet needs that deserve further efforts to improve long-term patients' outcomes and allow for a brighter future.
Topics: Amyloid Neuropathies, Familial; Gene Editing; Humans; Prealbumin; RNA Interference
PubMed: 34850359
DOI: 10.1007/s13311-021-01154-y -
International Journal of Biological... Jan 2021Tetrameric transthyretin (TTR) transports thyroid hormones and retinol in plasma and cerebrospinal fluid and performs protective functions under stress conditions....
Tetrameric transthyretin (TTR) transports thyroid hormones and retinol in plasma and cerebrospinal fluid and performs protective functions under stress conditions. Ageing and mutations result in TTR destabilisation and the formation of the amyloid deposits that dysregulate Ca homeostasis. Our aim was to determine whether Ca affects the structural stability of TTR. We show, using multiple techniques, that Ca does not induce prevalent TTR dissociation and/or oligomerisation. However, in the presence of Ca, TTR exhibits altered conformational flexibility and different interactions with the solvent molecules. These structural changes lead to the formation of the sub-populations of non-native TTR conformers and to the destabilisation of the structure of TTR. Moreover, the sub-population of TTR molecules undergoes fragmentation that is augmented by Ca. We postulate that Ca constitutes the structural and functional switch between the native and non-native forms of TTR, and therefore tip the balance towards age-dependent pathological calcification.
Topics: Calcium; Prealbumin; Protein Conformation; Protein Multimerization; Protein Stability
PubMed: 33129902
DOI: 10.1016/j.ijbiomac.2020.10.199 -
Singapore Medical Journal Jan 2023
Topics: Humans; Cardiomyopathies; Prealbumin
PubMed: 36722520
DOI: 10.4103/singaporemedj.SMJ-2021-300 -
Journal of Biological Regulators and...
Topics: Humans; Prealbumin; Urinary Bladder Neoplasms
PubMed: 33146006
DOI: 10.23812/20-230-L -
European Journal of Heart Failure Aug 2022
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Embolism; Heart Failure; Humans; Prealbumin
PubMed: 35790492
DOI: 10.1002/ejhf.2610 -
JACC. Heart Failure May 2021
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure; Humans; Prealbumin
PubMed: 33926733
DOI: 10.1016/j.jchf.2020.12.016 -
Circulation Apr 2024The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin...
BACKGROUND
The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome.
METHODS
Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality.
RESULTS
Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; <0.001), whereas Perugini grade was not associated with survival (=0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; <0.001), presence of the p.(V142I) variant (HR, 1.42 [95% CI, 1.20-1.81]; =0.004), National Amyloidosis Centre stage (each category, <0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; =0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; =0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; =0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; <0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; <0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM (<0.001 and =0.02, respectively).
CONCLUSIONS
Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis.
Topics: Humans; Cardiomyopathies; Prealbumin; Prognosis; Tomography, Emission-Computed, Single-Photon
PubMed: 38328945
DOI: 10.1161/CIRCULATIONAHA.123.066524