title: Bifunctional crosslinking ligands for transthyretin.
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.
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy.
authors.forename: P Patrizia
authors.initials: PP
authors.lastname: Mangione
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Deroo
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Ellmerich
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, Pavia, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Kolstoe
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Wood
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Carol V
authors.initials: CV
authors.lastname: Robinson
authors.affiliation: Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Smith
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Glenys A
authors.initials: GA
authors.lastname: Tennent
authors.affiliation: Peptide Protein Research Ltd, Claylands Road, Bishops Waltham, Southampton, Hampshire SO32 1QD, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Broadbridge
authors.affiliation: Peptide Protein Research Ltd, Claylands Road, Bishops Waltham, Southampton, Hampshire SO32 1QD, UK.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Council
authors.affiliation: Peptide Protein Research Ltd, Claylands Road, Bishops Waltham, Southampton, Hampshire SO32 1QD, UK.
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Thurston
authors.affiliation: Selcia Ltd, Fyfield Road, Ongar, Essex CM5 0GS, UK.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Steadman
authors.affiliation: Selcia Ltd, Fyfield Road, Ongar, Essex CM5 0GS, UK.
authors.forename: Antonio K
authors.initials: AK
authors.lastname: Vong
authors.affiliation: Cambridge MedChem Consulting, 8 Mangers Lane, Duxford, Cambridge CB22 4RN, UK.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Swain
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK.
authors.forename: Mark B
authors.initials: MB
authors.lastname: Pepys
authors.affiliation: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK graham.taylor@ucl.ac.uk.
authors.forename: Graham W
authors.initials: GW
authors.lastname: Taylor
mesh_terms: D000818:Animals; D001665:Binding Sites; D003432:Cross-Linking Reagents / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry; D011228:Prealbumin / Q000737:chemistry / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D013974:Thyroxine / Q000737:chemistry / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D008024:Ligands; D010880:Piperidines; D011228:Prealbumin; C032727:piperidine; D013974:Thyroxine
keywords: amyloidosis; crosslinking; plasma clearance; transthyretin