Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel

Abstract Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloid fibrillogenesis. It is modelled by exposure of the protein to non-physiological low pH in vitro and is inhibited by small molecule compounds, such as the drug tafamidis. We have re...

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Autores principales:	Guglielmo Verona, P. Patrizia Mangione, Sara Raimondi, Sofia Giorgetti, Giulia Faravelli, Riccardo Porcari, Alessandra Corazza, Julian D. Gillmore, Philip N. Hawkins, Mark B. Pepys, Graham W. Taylor, Vittorio Bellotti
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Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f338b2bcadbe45189416b0237ad95585
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spelling	oai:doaj.org-article:f338b2bcadbe45189416b0237ad955852021-12-02T12:32:36ZInhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel10.1038/s41598-017-00338-x2045-2322https://doaj.org/article/f338b2bcadbe45189416b0237ad955852017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00338-xhttps://doaj.org/toc/2045-2322Abstract Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloid fibrillogenesis. It is modelled by exposure of the protein to non-physiological low pH in vitro and is inhibited by small molecule compounds, such as the drug tafamidis. We have recently identified a new mechano-enzymatic pathway of TTR fibrillogenesis in vitro, catalysed by selective proteolytic cleavage, which produces a high yield of genuine amyloid fibrils. This pathway is efficiently inhibited only by ligands that occupy both binding sites in TTR. Tolcapone, which is bound with similar high affinity in both TTR binding sites without the usual negative cooperativity, is therefore of interest. Here we show that TTR fibrillogenesis by the mechano-enzymatic pathway is indeed more potently inhibited by tolcapone than by tafamidis but neither, even in large molar excess, completely prevents amyloid fibril formation. In contrast, mds84, the prototype of our previously reported bivalent ligand TTR ‘superstabiliser’ family, is notably more potent than the monovalent ligands and we show here that this apparently reflects the critical additional interactions of its linker within the TTR central channel. Our findings have major implications for therapeutic approaches in TTR amyloidosis.Guglielmo VeronaP. Patrizia MangioneSara RaimondiSofia GiorgettiGiulia FaravelliRiccardo PorcariAlessandra CorazzaJulian D. GillmorePhilip N. HawkinsMark B. PepysGraham W. TaylorVittorio BellottiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-7 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Guglielmo Verona P. Patrizia Mangione Sara Raimondi Sofia Giorgetti Giulia Faravelli Riccardo Porcari Alessandra Corazza Julian D. Gillmore Philip N. Hawkins Mark B. Pepys Graham W. Taylor Vittorio Bellotti Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel
description	Abstract Dissociation of the native transthyretin (TTR) tetramer is widely accepted as the critical step in TTR amyloid fibrillogenesis. It is modelled by exposure of the protein to non-physiological low pH in vitro and is inhibited by small molecule compounds, such as the drug tafamidis. We have recently identified a new mechano-enzymatic pathway of TTR fibrillogenesis in vitro, catalysed by selective proteolytic cleavage, which produces a high yield of genuine amyloid fibrils. This pathway is efficiently inhibited only by ligands that occupy both binding sites in TTR. Tolcapone, which is bound with similar high affinity in both TTR binding sites without the usual negative cooperativity, is therefore of interest. Here we show that TTR fibrillogenesis by the mechano-enzymatic pathway is indeed more potently inhibited by tolcapone than by tafamidis but neither, even in large molar excess, completely prevents amyloid fibril formation. In contrast, mds84, the prototype of our previously reported bivalent ligand TTR ‘superstabiliser’ family, is notably more potent than the monovalent ligands and we show here that this apparently reflects the critical additional interactions of its linker within the TTR central channel. Our findings have major implications for therapeutic approaches in TTR amyloidosis.
format	article
author	Guglielmo Verona P. Patrizia Mangione Sara Raimondi Sofia Giorgetti Giulia Faravelli Riccardo Porcari Alessandra Corazza Julian D. Gillmore Philip N. Hawkins Mark B. Pepys Graham W. Taylor Vittorio Bellotti
author_facet	Guglielmo Verona P. Patrizia Mangione Sara Raimondi Sofia Giorgetti Giulia Faravelli Riccardo Porcari Alessandra Corazza Julian D. Gillmore Philip N. Hawkins Mark B. Pepys Graham W. Taylor Vittorio Bellotti
author_sort	Guglielmo Verona
title	Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel
title_short	Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel
title_full	Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel
title_fullStr	Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel
title_full_unstemmed	Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel
title_sort	inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/f338b2bcadbe45189416b0237ad95585
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Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel

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