Trapping of palindromic ligands within native transthyretin prevents amyloid formation
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'-(undeca...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2010-11, Vol.107 (47), p.20483-20488 |
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| creator | Kolstoe, Simon E. Mangione, Palma P. Bellotti, Vittorio Taylor, Graham W. Tennent, Glenys A. Deroo, Stéphanie Morrison, Angus J. Cobb, Alexander J. A. Coyne, Anthony McCammon, Margaret G. Warner, Timothy D. Mitchell, Jane Gill, Raj Smith, Martin D. Ley, Steven V. Robinson, Carol V. Wood, Stephen P. Pepys, Mark B. Weatherall, David J. |
| description | 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. |
| doi_str_mv | 10.1073/pnas.1008255107 |
| format | Article |
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A. ; Coyne, Anthony ; McCammon, Margaret G. ; Warner, Timothy D. ; Mitchell, Jane ; Gill, Raj ; Smith, Martin D. ; Ley, Steven V. ; Robinson, Carol V. ; Wood, Stephen P. ; Pepys, Mark B. ; Weatherall, David J.</creator><creatorcontrib>Kolstoe, Simon E. ; Mangione, Palma P. ; Bellotti, Vittorio ; Taylor, Graham W. ; Tennent, Glenys A. ; Deroo, Stéphanie ; Morrison, Angus J. ; Cobb, Alexander J. A. ; Coyne, Anthony ; McCammon, Margaret G. ; Warner, Timothy D. ; Mitchell, Jane ; Gill, Raj ; Smith, Martin D. ; Ley, Steven V. ; Robinson, Carol V. ; Wood, Stephen P. ; Pepys, Mark B. ; Weatherall, David J.</creatorcontrib><description>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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1008255107</identifier><identifier>PMID: 21059958</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Aggregation ; Amyloid ; Amyloid - biosynthesis ; Amyloid - metabolism ; Amyloidogenesis ; Amyloidosis ; Amyloidosis - drug therapy ; Amyloidosis - metabolism ; Amyloids ; Animals ; Binding sites ; Biological Sciences ; Calorimetry, Differential Scanning ; Cells ; Chromatography, Gel ; Crystallography ; Crystallography, X-Ray ; Drug development ; Drug therapy ; Electron density ; Familial amyloidosis ; Fenamates - chemical synthesis ; Fenamates - chemistry ; Fenamates - metabolism ; Fenamates - pharmacokinetics ; Fluorescence ; Fluorometry ; Ionizing radiation ; Ligands ; Mass Spectrometry ; Mice ; Models, Molecular ; Molecular Structure ; Molecules ; Phospholipids ; Physiology ; Prealbumin - metabolism ; Prostaglandin-endoperoxide synthase ; Proteins ; Teeth ; transthyretin ; Trapping ; Ultracentrifugation</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-11, Vol.107 (47), p.20483-20488</ispartof><rights>Copyright National Academy of Sciences Nov 23, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c596t-e6dd82e2301dd6030653472f429d305884d2ee70536b24361c63d8bedcbe3a033</citedby><cites>FETCH-LOGICAL-c596t-e6dd82e2301dd6030653472f429d305884d2ee70536b24361c63d8bedcbe3a033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/107/47.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25756723$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25756723$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21059958$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kolstoe, Simon E.</creatorcontrib><creatorcontrib>Mangione, Palma P.</creatorcontrib><creatorcontrib>Bellotti, Vittorio</creatorcontrib><creatorcontrib>Taylor, Graham W.</creatorcontrib><creatorcontrib>Tennent, Glenys A.</creatorcontrib><creatorcontrib>Deroo, Stéphanie</creatorcontrib><creatorcontrib>Morrison, Angus J.</creatorcontrib><creatorcontrib>Cobb, Alexander J. A.</creatorcontrib><creatorcontrib>Coyne, Anthony</creatorcontrib><creatorcontrib>McCammon, Margaret G.</creatorcontrib><creatorcontrib>Warner, Timothy D.</creatorcontrib><creatorcontrib>Mitchell, Jane</creatorcontrib><creatorcontrib>Gill, Raj</creatorcontrib><creatorcontrib>Smith, Martin D.</creatorcontrib><creatorcontrib>Ley, Steven V.</creatorcontrib><creatorcontrib>Robinson, Carol V.</creatorcontrib><creatorcontrib>Wood, Stephen P.</creatorcontrib><creatorcontrib>Pepys, Mark B.</creatorcontrib><creatorcontrib>Weatherall, David J.</creatorcontrib><title>Trapping of palindromic ligands within native transthyretin prevents amyloid formation</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Aggregation</subject><subject>Amyloid</subject><subject>Amyloid - biosynthesis</subject><subject>Amyloid - metabolism</subject><subject>Amyloidogenesis</subject><subject>Amyloidosis</subject><subject>Amyloidosis - drug therapy</subject><subject>Amyloidosis - metabolism</subject><subject>Amyloids</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Biological Sciences</subject><subject>Calorimetry, Differential Scanning</subject><subject>Cells</subject><subject>Chromatography, Gel</subject><subject>Crystallography</subject><subject>Crystallography, X-Ray</subject><subject>Drug development</subject><subject>Drug therapy</subject><subject>Electron density</subject><subject>Familial amyloidosis</subject><subject>Fenamates - chemical synthesis</subject><subject>Fenamates - chemistry</subject><subject>Fenamates - metabolism</subject><subject>Fenamates - pharmacokinetics</subject><subject>Fluorescence</subject><subject>Fluorometry</subject><subject>Ionizing radiation</subject><subject>Ligands</subject><subject>Mass Spectrometry</subject><subject>Mice</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Molecules</subject><subject>Phospholipids</subject><subject>Physiology</subject><subject>Prealbumin - metabolism</subject><subject>Prostaglandin-endoperoxide synthase</subject><subject>Proteins</subject><subject>Teeth</subject><subject>transthyretin</subject><subject>Trapping</subject><subject>Ultracentrifugation</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkc1vEzEQxS0EoqFw5gRacelp6fhz7QtSVVFAqtRLy9Vy1t7E0a692Jug_Pd4ldBATz15NP7N05t5CL3H8BlDQy_HYHKpQBLOS-MFWmBQuBZMwUu0ACBNLRlhZ-hNzhsAUFzCa3RGMHBV6gX6eZ_MOPqwqmJXjab3waY4-Lbq_coEm6vfflr7UAUz-Z2rpmRCntb75KbSHJPbuTDlygz7PnpbdTENBYzhLXrVmT67d8f3HD3cfL2__l7f3n37cX11W7dcial2wlpJHKGArRVAQXDKGtIxoiwFLiWzxLkGOBVLwqjAraBWLp1tl44aoPQcfTnojtvlUNrFTTK9HpMfTNrraLz-_yf4tV7FnSZKCSGhCFwcBVL8tXV50oPPret7E1zcZi2Vwoxg8gyyUaw4xbyQn56Qm7hNodxBS1y2UAJmucsD1KaYc3Ldo2kMes5Wz9nqU7Zl4uO_uz7yf8MsQHUE5smTXKNZowkwOd_rwwHZ5CmmkwRvuGgIpX8AUK-1VQ</recordid><startdate>20101123</startdate><enddate>20101123</enddate><creator>Kolstoe, Simon E.</creator><creator>Mangione, Palma P.</creator><creator>Bellotti, Vittorio</creator><creator>Taylor, Graham W.</creator><creator>Tennent, Glenys A.</creator><creator>Deroo, Stéphanie</creator><creator>Morrison, Angus J.</creator><creator>Cobb, Alexander J. 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A. ; Coyne, Anthony ; McCammon, Margaret G. ; Warner, Timothy D. ; Mitchell, Jane ; Gill, Raj ; Smith, Martin D. ; Ley, Steven V. ; Robinson, Carol V. ; Wood, Stephen P. ; Pepys, Mark B. ; Weatherall, David J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c596t-e6dd82e2301dd6030653472f429d305884d2ee70536b24361c63d8bedcbe3a033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Aggregation</topic><topic>Amyloid</topic><topic>Amyloid - biosynthesis</topic><topic>Amyloid - metabolism</topic><topic>Amyloidogenesis</topic><topic>Amyloidosis</topic><topic>Amyloidosis - drug therapy</topic><topic>Amyloidosis - metabolism</topic><topic>Amyloids</topic><topic>Animals</topic><topic>Binding sites</topic><topic>Biological Sciences</topic><topic>Calorimetry, Differential Scanning</topic><topic>Cells</topic><topic>Chromatography, Gel</topic><topic>Crystallography</topic><topic>Crystallography, X-Ray</topic><topic>Drug development</topic><topic>Drug therapy</topic><topic>Electron density</topic><topic>Familial amyloidosis</topic><topic>Fenamates - chemical synthesis</topic><topic>Fenamates - chemistry</topic><topic>Fenamates - metabolism</topic><topic>Fenamates - pharmacokinetics</topic><topic>Fluorescence</topic><topic>Fluorometry</topic><topic>Ionizing radiation</topic><topic>Ligands</topic><topic>Mass Spectrometry</topic><topic>Mice</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Molecules</topic><topic>Phospholipids</topic><topic>Physiology</topic><topic>Prealbumin - metabolism</topic><topic>Prostaglandin-endoperoxide synthase</topic><topic>Proteins</topic><topic>Teeth</topic><topic>transthyretin</topic><topic>Trapping</topic><topic>Ultracentrifugation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kolstoe, Simon E.</creatorcontrib><creatorcontrib>Mangione, Palma P.</creatorcontrib><creatorcontrib>Bellotti, Vittorio</creatorcontrib><creatorcontrib>Taylor, Graham W.</creatorcontrib><creatorcontrib>Tennent, Glenys A.</creatorcontrib><creatorcontrib>Deroo, Stéphanie</creatorcontrib><creatorcontrib>Morrison, Angus J.</creatorcontrib><creatorcontrib>Cobb, Alexander J. 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A.</au><au>Coyne, Anthony</au><au>McCammon, Margaret G.</au><au>Warner, Timothy D.</au><au>Mitchell, Jane</au><au>Gill, Raj</au><au>Smith, Martin D.</au><au>Ley, Steven V.</au><au>Robinson, Carol V.</au><au>Wood, Stephen P.</au><au>Pepys, Mark B.</au><au>Weatherall, David J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Trapping of palindromic ligands within native transthyretin prevents amyloid formation</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2010-11-23</date><risdate>2010</risdate><volume>107</volume><issue>47</issue><spage>20483</spage><epage>20488</epage><pages>20483-20488</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21059958</pmid><doi>10.1073/pnas.1008255107</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aggregation Amyloid Amyloid - biosynthesis Amyloid - metabolism Amyloidogenesis Amyloidosis Amyloidosis - drug therapy Amyloidosis - metabolism Amyloids Animals Binding sites Biological Sciences Calorimetry, Differential Scanning Cells Chromatography, Gel Crystallography Crystallography, X-Ray Drug development Drug therapy Electron density Familial amyloidosis Fenamates - chemical synthesis Fenamates - chemistry Fenamates - metabolism Fenamates - pharmacokinetics Fluorescence Fluorometry Ionizing radiation Ligands Mass Spectrometry Mice Models, Molecular Molecular Structure Molecules Phospholipids Physiology Prealbumin - metabolism Prostaglandin-endoperoxide synthase Proteins Teeth transthyretin Trapping Ultracentrifugation |
| title | Trapping of palindromic ligands within native transthyretin prevents amyloid formation |
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