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 precu...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Royal Society
2015-01-01
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| Series: | Open Biology |
| Subjects: | |
| Online Access: | https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.150105 |
| _version_ | 1818720133094309888 |
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| author | P. Patrizia Mangione Stéphanie Deroo Stephan Ellmerich Vittorio Bellotti Simon Kolstoe Stephen P. Wood Carol V. Robinson Martin D. Smith Glenys A. Tennent Robert J. Broadbridge Claire E. Council Joanne R. Thurston Victoria A. Steadman Antonio K. Vong Christopher J. Swain Mark B. Pepys Graham W. Taylor |
| author_facet | P. Patrizia Mangione Stéphanie Deroo Stephan Ellmerich Vittorio Bellotti Simon Kolstoe Stephen P. Wood Carol V. Robinson Martin D. Smith Glenys A. Tennent Robert J. Broadbridge Claire E. Council Joanne R. Thurston Victoria A. Steadman Antonio K. Vong Christopher J. Swain Mark B. Pepys Graham W. Taylor |
| author_sort | P. Patrizia Mangione |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T20:17:59Z |
| format | Article |
| id | doaj.art-92a745814544494abf587c612d2605eb |
| institution | Directory Open Access Journal |
| issn | 2046-2441 |
| language | English |
| last_indexed | 2024-12-17T20:17:59Z |
| publishDate | 2015-01-01 |
| publisher | The Royal Society |
| record_format | Article |
| series | Open Biology |
| spelling | doaj.art-92a745814544494abf587c612d2605eb2022-12-21T21:34:02ZengThe Royal SocietyOpen Biology2046-24412015-01-015910.1098/rsob.150105150105Bifunctional crosslinking ligands for transthyretinP. Patrizia MangioneStéphanie DerooStephan EllmerichVittorio BellottiSimon KolstoeStephen P. WoodCarol V. RobinsonMartin D. SmithGlenys A. TennentRobert J. BroadbridgeClaire E. CouncilJoanne R. ThurstonVictoria A. SteadmanAntonio K. VongChristopher J. SwainMark B. PepysGraham W. TaylorWild-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.https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.150105amyloidosistransthyretincrosslinkingplasma clearance |
| spellingShingle | P. Patrizia Mangione Stéphanie Deroo Stephan Ellmerich Vittorio Bellotti Simon Kolstoe Stephen P. Wood Carol V. Robinson Martin D. Smith Glenys A. Tennent Robert J. Broadbridge Claire E. Council Joanne R. Thurston Victoria A. Steadman Antonio K. Vong Christopher J. Swain Mark B. Pepys Graham W. Taylor Bifunctional crosslinking ligands for transthyretin Open Biology amyloidosis transthyretin crosslinking plasma clearance |
| title | Bifunctional crosslinking ligands for transthyretin |
| title_full | Bifunctional crosslinking ligands for transthyretin |
| title_fullStr | Bifunctional crosslinking ligands for transthyretin |
| title_full_unstemmed | Bifunctional crosslinking ligands for transthyretin |
| title_short | Bifunctional crosslinking ligands for transthyretin |
| title_sort | bifunctional crosslinking ligands for transthyretin |
| topic | amyloidosis transthyretin crosslinking plasma clearance |
| url | https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.150105 |
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