Trapping of palindromic ligands within native transthyretin prevents amyloid formation

Simon E. Kolstoe; Palma P. Mangione; Vittorio Bellotti; Graham W. Taylor; Glenys A. Tennent; Stephanie Deroo; Angus J. Morrison; Alexander J. A. Cobb; Anthony Coyne; Margaret G. McCammon; Timothy D. Warner; Jane Mitchell; Raj Gill; Martin D. Smith; Steven V. Ley; Carol V. Robinson; Stephen P. Wood; Mark B. Pepys

doi:10.1073/pnas.1008255107

Trapping of palindromic ligands within native transthyretin prevents amyloid formation

Simon E. Kolstoe, Palma P. Mangione, Vittorio Bellotti, Graham W. Taylor, Glenys A. Tennent, Stephanie Deroo, Angus J. Morrison, Alexander J. A. Cobb, Anthony Coyne, Margaret G. McCammon, Timothy D. Warner, Jane Mitchell, Raj Gill, Martin D. Smith, Steven V. Ley, Carol V. Robinson, Stephen P. Wood, Mark B. Pepys

Institute of Life Sciences and Healthcare

University of Oxford

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	20483-20488
Journal	Proceedings of the National Academy of Sciences
Volume	107
Issue number	47
DOIs	https://doi.org/10.1073/pnas.1008255107
Publication status	Published - 23 Nov 2010

Keywords

crystallography
mass spectrometry
protein structure
stabilization

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Kolstoe, 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, C. V., Wood, S. P., & Pepys, M. B. (2010). Trapping of palindromic ligands within native transthyretin prevents amyloid formation. Proceedings of the National Academy of Sciences, 107(47), 20483-20488. https://doi.org/10.1073/pnas.1008255107

@article{bdf570251c974c48a5413a7e98c343e6,

title = "Trapping of palindromic ligands within native transthyretin prevents amyloid formation",

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 = "crystallography, mass spectrometry, protein structure, stabilization",

author = "Kolstoe, {Simon E.} and Mangione, {Palma P.} and Vittorio Bellotti and Taylor, {Graham W.} and Tennent, {Glenys A.} and Stephanie Deroo and Morrison, {Angus J.} and Cobb, {Alexander J. A.} and Anthony Coyne and McCammon, {Margaret G.} and Warner, {Timothy D.} and Jane Mitchell and Raj Gill and Smith, {Martin D.} and Ley, {Steven V.} and Robinson, {Carol V.} and Wood, {Stephen P.} and Pepys, {Mark B.}",

year = "2010",

month = nov,

day = "23",

doi = "10.1073/pnas.1008255107",

language = "English",

volume = "107",

pages = "20483--20488",

journal = "Proceedings of the National Academy of Sciences",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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Kolstoe, SE, Mangione, PP, Bellotti, V, Taylor, GW, Tennent, GA, Deroo, S, Morrison, AJ, Cobb, AJA, Coyne, A, McCammon, MG, Warner, TD, Mitchell, J, Gill, R, Smith, MD, Ley, SV, Robinson, CV, Wood, SP & Pepys, MB 2010, 'Trapping of palindromic ligands within native transthyretin prevents amyloid formation', Proceedings of the National Academy of Sciences, vol. 107, no. 47, pp. 20483-20488. https://doi.org/10.1073/pnas.1008255107

TY - JOUR

T1 - Trapping of palindromic ligands within native transthyretin prevents amyloid formation

AU - Kolstoe, Simon E.

AU - Mangione, Palma P.

AU - Bellotti, Vittorio

AU - Taylor, Graham W.

AU - Tennent, Glenys A.

AU - Deroo, Stephanie

AU - Morrison, Angus J.

AU - Cobb, Alexander J. A.

AU - Coyne, Anthony

AU - McCammon, Margaret G.

AU - Warner, Timothy D.

AU - Mitchell, Jane

AU - Gill, Raj

AU - Smith, Martin D.

AU - Ley, Steven V.

AU - Robinson, Carol V.

AU - Wood, Stephen P.

AU - Pepys, Mark B.

PY - 2010/11/23

Y1 - 2010/11/23

N2 - 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.

AB - 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.

KW - crystallography

KW - mass spectrometry

KW - protein structure

KW - stabilization

U2 - 10.1073/pnas.1008255107

DO - 10.1073/pnas.1008255107

M3 - Article

SN - 0027-8424

VL - 107

SP - 20483

EP - 20488

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

IS - 47

ER -

Trapping of palindromic ligands within native transthyretin prevents amyloid formation

Abstract

Keywords

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