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Trapping of palindromic ligands within native transthyretin prevents amyloid formation

journal contribution
posted on 2023-06-09, 04:36 authored by Simon E Kolstoe, Palma P Mangione, Vittorio Bellotti, Graham W Taylor, Glenys A Tennent, Stéphanie 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, Caron P Robinson, Stephen P Wood, Mark B Pepys
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.

History

Publication status

  • Published

Journal

Proceedings of the National Academy of Sciences

ISSN

0027-8424

Publisher

National Academy of Sciences

Issue

47

Volume

107

Page range

20483-20488

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2017-01-09

First Compliant Deposit (FCD) Date

2017-01-09

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