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Trapping of palindromic ligands within native transthyretin prevents amyloid formation

DOI: 10.1073/pnas.1008255107 DOI Help
PMID: 21059958 PMID Help

Authors: Simon E. Kolstoe (University College London Medical School) , Palma P. Mangione (University College London Medical School; Università di Pavia) , Vittorio Bellotti (University College London Medical School; Università di Pavia) , Graham W. Taylor (University College London Medical School) , Glenys A. Tennent (University College London Medical School) , Stéphanie Deroo (University of Cambridge) , Angus J. Morrison (University of Cambridge) , Alexander J. A. Cobb (University of Cambridge) , Anthony Coyne (University of Cambridge) , Margaret Mccammon (University of Cambridge) , Timothy D. Warner (William Harvey Research Institute; The London Queen Mary’s School of Medicine and Dentistry) , Jane Mitchell (William Harvey Research Institute; The London Queen Mary’s School of Medicine and Dentistry) , Raj Gill (Royal Free and University College Medical School) , Martin D. Smith (University of Oxford) , Steven Ley (University of Cambridge) , Carol V. Robinson (University of Cambridge) , Stephen P. Wood (University College London Medical School) , Mark B. Pepys (University College London Medical School)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 107(47) , PAGES 20483-20488

State: Published (Approved)
Published: November 2010

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.

Journal Keywords: Amyloidosis; Animals; Calorimetry; Differential; Chromatography; Gel; Crystallography; X-Ray; Fenamates; Fluorometry; Ligands; Mass; Mice; Models; Molecular; Prealbumin; Ultracentrifugation

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography