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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.

Original publication

DOI

10.1073/pnas.1008255107

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

23/11/2010

Volume

107

Pages

20483 - 20488

Keywords

Amyloid, Amyloidosis, Animals, Calorimetry, Differential Scanning, Chromatography, Gel, Crystallography, X-Ray, Fenamates, Fluorometry, Ligands, Mass Spectrometry, Mice, Models, Molecular, Molecular Structure, Prealbumin, Ultracentrifugation