The University of Southampton
University of Southampton Institutional Repository

Bifunctional crosslinking ligands for transthyretin.

Bifunctional crosslinking ligands for transthyretin.
Bifunctional crosslinking ligands for transthyretin.
Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR–ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.
Mangione, P. Patrizia
f7e2aff2-1d17-45a7-8607-422919c4c08a
Deroo, Stéphanie
731def70-6231-446b-8dd6-24368ca2d0ac
Ellmerich, Stephan
686bc21d-4d14-4af3-83aa-25d4994710ad
Bellotti, Vittorio
1463de43-7e5c-47cb-b712-c38aa65fafe7
Kolstoe, Simon
de650d4a-6146-4094-bdb0-97693e158ad3
Wood, Stephen P.
a99e099c-bc18-42ef-a5db-673640c63fec
Robinson, Carol V.
316e8169-6203-418c-bc4f-9baf13074768
Smith, Martin D.
39709d8b-b84d-498b-880a-8280f7ac8135
Tennent, Glenys A.
fa3dd409-456d-46be-b9bd-dd4078f79b08
Broadbridge, Robert J.
ce42ee45-e84a-47ec-9706-ef63bef12f2a
Council, Claire E.
d3b28ff6-e69a-4ec2-a4c8-99282a2609be
Thurston, Joanne R.
ccebf6fd-dd95-4abe-869c-5f606c370008
Steadman, Victoria A.
81aa7651-c3c8-4d95-970e-19d3d9c53cb6
Vong, Antonio K.
e5ee1c63-75ef-4439-9a01-a20b4bfb8e40
Swain, Christopher J.
46cf31df-3413-492d-97a1-d263d5ed3f07
Pepys, Mark B.
ef08d680-ca7e-434f-a380-efce4058ba68
Taylor, Graham W.
a66fa3f3-96d4-499c-9230-a57596296bf5
Mangione, P. Patrizia
f7e2aff2-1d17-45a7-8607-422919c4c08a
Deroo, Stéphanie
731def70-6231-446b-8dd6-24368ca2d0ac
Ellmerich, Stephan
686bc21d-4d14-4af3-83aa-25d4994710ad
Bellotti, Vittorio
1463de43-7e5c-47cb-b712-c38aa65fafe7
Kolstoe, Simon
de650d4a-6146-4094-bdb0-97693e158ad3
Wood, Stephen P.
a99e099c-bc18-42ef-a5db-673640c63fec
Robinson, Carol V.
316e8169-6203-418c-bc4f-9baf13074768
Smith, Martin D.
39709d8b-b84d-498b-880a-8280f7ac8135
Tennent, Glenys A.
fa3dd409-456d-46be-b9bd-dd4078f79b08
Broadbridge, Robert J.
ce42ee45-e84a-47ec-9706-ef63bef12f2a
Council, Claire E.
d3b28ff6-e69a-4ec2-a4c8-99282a2609be
Thurston, Joanne R.
ccebf6fd-dd95-4abe-869c-5f606c370008
Steadman, Victoria A.
81aa7651-c3c8-4d95-970e-19d3d9c53cb6
Vong, Antonio K.
e5ee1c63-75ef-4439-9a01-a20b4bfb8e40
Swain, Christopher J.
46cf31df-3413-492d-97a1-d263d5ed3f07
Pepys, Mark B.
ef08d680-ca7e-434f-a380-efce4058ba68
Taylor, Graham W.
a66fa3f3-96d4-499c-9230-a57596296bf5

Mangione, P. Patrizia, Deroo, Stéphanie, Ellmerich, Stephan, Bellotti, Vittorio, Kolstoe, Simon, Wood, Stephen P., Robinson, Carol V., Smith, Martin D., Tennent, Glenys A., Broadbridge, Robert J., Council, Claire E., Thurston, Joanne R., Steadman, Victoria A., Vong, Antonio K., Swain, Christopher J., Pepys, Mark B. and Taylor, Graham W. (2015) Bifunctional crosslinking ligands for transthyretin. Open Biology, 5, [150105]. (doi:10.1098/rsob.150105).

Record type: Article

Abstract

Wild-type and variant forms of transthyretin (TTR), a normal plasma protein, are amyloidogenic and can be deposited in the tissues as amyloid fibrils causing acquired and hereditary systemic TTR amyloidosis, a debilitating and usually fatal disease. Reduction in the abundance of amyloid fibril precursor proteins arrests amyloid deposition and halts disease progression in all forms of amyloidosis including TTR type. Our previous demonstration that circulating serum amyloid P component (SAP) is efficiently depleted by administration of a specific small molecule ligand compound, that non-covalently crosslinks pairs of SAP molecules, suggested that TTR may be also amenable to this approach. We first confirmed that chemically crosslinked human TTR is rapidly cleared from the circulation in mice. In order to crosslink pairs of TTR molecules, promote their accelerated clearance and thus therapeutically deplete plasma TTR, we prepared a range of bivalent specific ligands for the thyroxine binding sites of TTR. Non-covalently bound human TTR–ligand complexes were formed that were stable in vitro and in vivo, but they were not cleared from the plasma of mice in vivo more rapidly than native uncomplexed TTR. Therapeutic depletion of circulating TTR will require additional mechanisms.

Text
mangione-et-al-2015-bifunctional-crosslinking-ligands-for-transthyretin - Version of Record
Available under License Creative Commons Attribution.
Download (780kB)

More information

e-pub ahead of print date: 1 September 2015

Identifiers

Local EPrints ID: 491281
URI: http://eprints.soton.ac.uk/id/eprint/491281
PURE UUID: 1623ff84-85f7-4ee2-99bf-6ef60ba313f9
ORCID for Claire E. Council: ORCID iD orcid.org/0000-0003-0600-4689

Catalogue record

Date deposited: 18 Jun 2024 16:58
Last modified: 22 Jun 2024 01:57

Export record

Altmetrics

Contributors

Author: P. Patrizia Mangione
Author: Stéphanie Deroo
Author: Stephan Ellmerich
Author: Vittorio Bellotti
Author: Simon Kolstoe
Author: Stephen P. Wood
Author: Carol V. Robinson
Author: Martin D. Smith
Author: Glenys A. Tennent
Author: Robert J. Broadbridge
Author: Claire E. Council ORCID iD
Author: Joanne R. Thurston
Author: Victoria A. Steadman
Author: Antonio K. Vong
Author: Christopher J. Swain
Author: Mark B. Pepys
Author: Graham W. Taylor

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×