ArticleProceedings of the National Academy of Sciences of the United States of America2010
Trapping of palindromic ligands within native transthyretin prevents amyloid formation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 65 citations in OpenAlex.
- Induced Circular Dichroism From the Binding of Achiral Bivalent Ligands to Transthyretin.Journal of molecular recognition : JMR · 2026Article
- Design and Mechanistic Analysis of a Potent Bivalent Inhibitor of Transthyretin Amyloid Fibrillogenesis.Journal of medicinal chemistry · 2025Article
- Fragment-based drug discovery for transthyretin kinetic stabilisers using a novel capillary zone electrophoresis method.PloS one · 2025Article
- Inhibitors of Transthyretin Amyloidosis: How to Rank Drug Candidates Using X-ray Crystallography Data.Molecules (Basel, Switzerland) · 2024Article
- A Comprehensive Review on Chemistry and Biology of Tafamidis in Transthyretin Amyloidosis.Mini reviews in medicinal chemistry · 2024Review
- Binding of a Pyrene-Based Fluorescent Amyloid Ligand to Transthyretin: A Combined Crystallographic and Molecular Dynamics Study.The journal of physical chemistry. B · 2023Article
- Discovery of Dual Aβ/Tau Inhibitors and Evaluation of Their Therapeutic Effect on aACS chemical neuroscience · 2022Article
- Targeted treatments of AL and ATTR amyloidosis.Heart failure reviews · 2022Review
- Transthyretin Misfolding, A Fatal Structural Pathogenesis Mechanism.International journal of molecular sciences · 2021Review
- Modulation of the Mechanisms Driving Transthyretin Amyloidosis.Frontiers in molecular neuroscience · 2020Review
- Treating Protein Misfolding Diseases: Therapeutic Successes Against Systemic Amyloidoses.Frontiers in pharmacology · 2020Review
- Binding of Monovalent and Bivalent Ligands by Transthyretin Causes Different Short- and Long-Distance Conformational Changes.Journal of medicinal chemistry · 2019Article
- 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
- Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel.Scientific reports · 2017Article
- Oleuropein aglycone and polyphenols from olive mill waste water ameliorate cognitive deficits and neuropathology.British journal of clinical pharmacology · 2017Review
- Disorder transitions and conformational diversity cooperatively modulate biological function in proteins.Protein science : a publication of the Protein Society · 2016Article
- Substoichiometric inhibition of transthyretin misfolding by immune-targeting sparsely populated misfolding intermediates: a potential diagnostic and therapeutic for TTR amyloidoses.Scientific reports · 2016Article
- Transthyretin Binding Heterogeneity and Anti-amyloidogenic Activity of Natural Polyphenols and Their Metabolites.The Journal of biological chemistry · 2015Article
- A novel mechano-enzymatic cleavage mechanism underlies transthyretin amyloidogenesis.EMBO molecular medicine · 2015Article
- Bifunctional crosslinking ligands for transthyretin.Open biology · 2015Article
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Authors and funding
18 authors at 5 institutions in 2 countries.
Funding
Abstract
Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, 2,2'-(4,4'-(heptane-1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2'-(4,4'-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis.
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Registered trials
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