ArticleScientific reports2017
Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 39 citations in OpenAlex.
- Differentiating the solution structures and stability of transthyretin tetramer complexed with tolcapone and tafamidis using SEC-SWAXS and NMR.Journal of applied crystallography · 2025Article
- Design and Mechanistic Analysis of a Potent Bivalent Inhibitor of Transthyretin Amyloid Fibrillogenesis.Journal of medicinal chemistry · 2025Article
- Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence.The Egyptian heart journal : (EHJ) : official bulletin of the Egyptian Society of Cardiology · 2024Review
- A Comprehensive Review on Chemistry and Biology of Tafamidis in Transthyretin Amyloidosis.Mini reviews in medicinal chemistry · 2024Review
- 3-O-Methyltolcapone and Its Lipophilic Analogues Are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity.International journal of molecular sciences · 2023Article
- Transient On- and Off-Pathway Protein Folding Intermediate States Characterized with NMR Relaxation Dispersion.The journal of physical chemistry. B · 2022Article
- Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation.Journal of medicinal chemistry · 2022Article
- Targeted treatments of AL and ATTR amyloidosis.Heart failure reviews · 2022Review
- Treatment of Transthyretin Amyloid Cardiomyopathy: The Current Options, the Future, and the Challenges.Journal of clinical medicine · 2022Review
- Amyloid fibril composition type is consistent over time in patients with Val30Met (p.Val50Met) transthyretin amyloidosis.PloS one · 2022Article
- Current and Emerging Therapies for Hereditary Transthyretin Amyloidosis: Strides Towards a Brighter Future.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2021Review
- Breakdown of supersaturation barrier links protein folding to amyloid formation.Communications biology · 2021Article
- Modulation of the Mechanisms Driving Transthyretin Amyloidosis.Frontiers in molecular neuroscience · 2020Review
- Binding of Monovalent and Bivalent Ligands by Transthyretin Causes Different Short- and Long-Distance Conformational Changes.Journal of medicinal chemistry · 2019Article
- Plasminogen activation triggers transthyretin amyloidogenesisThe Journal of biological chemistry · 2018Article
- Targeting Amyloid Aggregation: An Overview of Strategies and Mechanisms.International journal of molecular sciences · 2018Review
- Unusual duplication mutation in a surface loop of human transthyretin leads to an aggressive drug-resistant amyloid disease.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
Abstract
Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloid fibrillogenesis. It is modelled by exposure of the protein to non-physiological low pH in vitro and is inhibited by small molecule compounds, such as the drug tafamidis. We have recently identified a new mechano-enzymatic pathway of TTR fibrillogenesis in vitro, catalysed by selective proteolytic cleavage, which produces a high yield of genuine amyloid fibrils. This pathway is efficiently inhibited only by ligands that occupy both binding sites in TTR. Tolcapone, which is bound with similar high affinity in both TTR binding sites without the usual negative cooperativity, is therefore of interest. Here we show that TTR fibrillogenesis by the mechano-enzymatic pathway is indeed more potently inhibited by tolcapone than by tafamidis but neither, even in large molar excess, completely prevents amyloid fibril formation. In contrast, mds84, the prototype of our previously reported bivalent ligand TTR 'superstabiliser' family, is notably more potent than the monovalent ligands and we show here that this apparently reflects the critical additional interactions of its linker within the TTR central channel. Our findings have major implications for therapeutic approaches in TTR amyloidosis.
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