Trapping of palindromic ligands within native transthyretin prevents amyloid formation
- 8 November 2010
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (47), 20483-20488
- https://doi.org/10.1073/pnas.1008255107
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.Keywords
This publication has 41 references indexed in Scilit:
- COX‐1, and not COX‐2 activity, regulates airway function: relevance to aspirin‐sensitive asthmaThe FASEB Journal, 2008
- Native State Kinetic Stabilization as a Strategy To Ameliorate Protein Misfolding Diseases: A Focus on the Transthyretin AmyloidosesAccounts of Chemical Research, 2005
- Coot: model-building tools for molecular graphicsActa Crystallographica Section D-Biological Crystallography, 2004
- Deuterium-proton exchange on the native wild-type transthyretin tetramer identifies the stable core of the individual subunits and indicates mobility at the subunit interfaceJournal of Molecular Biology, 2000
- Size-Distribution Analysis of Macromolecules by Sedimentation Velocity Ultracentrifugation and Lamm Equation ModelingBiophysical Journal, 2000
- Common core structure of amyloid fibrils by synchrotron X-ray diffraction 1 1Edited by F. E. CohenJournal of Molecular Biology, 1997
- Thyroxine binding to transthyretin Met 119Endocrine, 1997
- Refinement of Macromolecular Structures by the Maximum-Likelihood MethodActa Crystallographica Section D-Biological Crystallography, 1997
- Retinoid binding to retinol-binding protein and the interference with the interaction with transthyretinBiochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology, 1996
- Thyroxine interactions with transthyretin: a comparison of 10 different naturally occurring human transthyretin variantsJournal of Clinical Endocrinology & Metabolism, 1993