Trapping of palindromic ligands within native transthyretin prevents amyloid formationKolstoe, S. E., Mangione, P. P., Bellotti, V., Taylor, G. W., Tennent, G. A., Deroo, S., Morrison, A. J., Cobb, A. J. A., Coyne, A., McCammon, M. G., Warner, T. D., Mitchell, J., Gill, R., Smith, M. D., Ley, S. V., Robinson, S. P. and Pepys, M. B. (2010) Trapping of palindromic ligands within native transthyretin prevents amyloid formation. Proceedings of the National Academy of Sciences of the United States of America, 107 (47). pp. 20483-20488. ISSN 0027-8424 Full text not archived in this repository. It is advisable to refer to the publisher's version if you intend to cite from this work. See Guidance on citing. To link to this item DOI: 10.1073/pnas.1008255107 Abstract/SummaryTransthyretin (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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