Design, synthesis and evaluation of biomimetic affinity ligands for elastases
A low‐molecular‐weight biomimetic affinity ligand selective for binding elastase has been designed and synthesized. The ligand was based on mimicking part of the interaction between a natural inhibitor, turkey ovomucoid inhibitor and elastase, and modelled from the X‐ray crystallographic structure o...
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Veröffentlicht in: | Journal of molecular recognition 2000-11, Vol.13 (6), p.370-381 |
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creator | Filippusson, Hörður Erlendsson, Lýður S. Lowe, Christopher R. |
description | A low‐molecular‐weight biomimetic affinity ligand selective for binding elastase has been designed and synthesized. The ligand was based on mimicking part of the interaction between a natural inhibitor, turkey ovomucoid inhibitor and elastase, and modelled from the X‐ray crystallographic structure of the enzyme–inhibitor complex. Limited solid‐phase combinatorial chemistry was used to synthesize 12 variants of the lead ligand using the triazine moiety as the scaffold for assembly. The ligand library was screened for its ability to bind elastase and trypsin, and two ligands were studied further. Ligand C4/6 [2‐alanyl‐alanyl‐4‐tryptamino‐6‐(α‐lysyl)‐s‐triazine] was found to bind porcine pancreatic elastase, but not trypsin, with a dissociation constant of 6 × 10−5 M and a binding capacity of 21 mg elastase per ml gel. The adsorbent was used to purify elastase from a crude extract of porcine pancreas. Immobilized ligand C4/5 6 [2‐alanyl‐alanyl‐4‐tyramino‐6‐(α‐lysyl)‐s‐triazine] was similarly chosen for optimal binding of elastase from cod and used to purify the enzyme from a crude extract of cod pyloric caeca. Ligand C4/6 was subsequently synthesized in solution and its structure verified by 1H‐NMR. Copyright © 2000 John Wiley & Sons, Ltd.
Abbreviations used:
BAPNA
benzoyl arginine P‐nitroanilide
HLE
human leucocyte elastase
PPE
porcine pancreatic elastase. |
doi_str_mv | 10.1002/1099-1352(200011/12)13:6<370::AID-JMR510>3.0.CO;2-5 |
format | Article |
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Abbreviations used:
BAPNA
benzoyl arginine P‐nitroanilide
HLE
human leucocyte elastase
PPE
porcine pancreatic elastase.</description><identifier>ISSN: 0952-3499</identifier><identifier>EISSN: 1099-1352</identifier><identifier>DOI: 10.1002/1099-1352(200011/12)13:6<370::AID-JMR510>3.0.CO;2-5</identifier><identifier>PMID: 11114070</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>affinity chromatography ; Animals ; biomimetic ligands ; Chromatography, Affinity ; Drug Design ; elastase ; Fishes ; Ligands ; Models, Molecular ; Molecular Mimicry ; Oligopeptides - chemistry ; Oligopeptides - metabolism ; Pancreatic Elastase - chemistry ; Pancreatic Elastase - isolation & purification ; Pancreatic Elastase - metabolism ; serine proteinase ; Solutions ; Swine ; triazine</subject><ispartof>Journal of molecular recognition, 2000-11, Vol.13 (6), p.370-381</ispartof><rights>Copyright © 2000 John Wiley & Sons, Ltd.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c4000-e3bc3bff86616599f0529944793c877bb95e490333b3fc5d48fbac39540cf4e03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2F1099-1352%28200011%2F12%2913%3A6%3C370%3A%3AAID-JMR510%3E3.0.CO%3B2-5$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2F1099-1352%28200011%2F12%2913%3A6%3C370%3A%3AAID-JMR510%3E3.0.CO%3B2-5$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11114070$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Filippusson, Hörður</creatorcontrib><creatorcontrib>Erlendsson, Lýður S.</creatorcontrib><creatorcontrib>Lowe, Christopher R.</creatorcontrib><title>Design, synthesis and evaluation of biomimetic affinity ligands for elastases</title><title>Journal of molecular recognition</title><addtitle>J. Mol. Recognit</addtitle><description>A low‐molecular‐weight biomimetic affinity ligand selective for binding elastase has been designed and synthesized. The ligand was based on mimicking part of the interaction between a natural inhibitor, turkey ovomucoid inhibitor and elastase, and modelled from the X‐ray crystallographic structure of the enzyme–inhibitor complex. Limited solid‐phase combinatorial chemistry was used to synthesize 12 variants of the lead ligand using the triazine moiety as the scaffold for assembly. The ligand library was screened for its ability to bind elastase and trypsin, and two ligands were studied further. Ligand C4/6 [2‐alanyl‐alanyl‐4‐tryptamino‐6‐(α‐lysyl)‐s‐triazine] was found to bind porcine pancreatic elastase, but not trypsin, with a dissociation constant of 6 × 10−5 M and a binding capacity of 21 mg elastase per ml gel. The adsorbent was used to purify elastase from a crude extract of porcine pancreas. Immobilized ligand C4/5 6 [2‐alanyl‐alanyl‐4‐tyramino‐6‐(α‐lysyl)‐s‐triazine] was similarly chosen for optimal binding of elastase from cod and used to purify the enzyme from a crude extract of cod pyloric caeca. Ligand C4/6 was subsequently synthesized in solution and its structure verified by 1H‐NMR. Copyright © 2000 John Wiley & Sons, Ltd.
Abbreviations used:
BAPNA
benzoyl arginine P‐nitroanilide
HLE
human leucocyte elastase
PPE
porcine pancreatic elastase.</description><subject>affinity chromatography</subject><subject>Animals</subject><subject>biomimetic ligands</subject><subject>Chromatography, Affinity</subject><subject>Drug Design</subject><subject>elastase</subject><subject>Fishes</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Molecular Mimicry</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - metabolism</subject><subject>Pancreatic Elastase - chemistry</subject><subject>Pancreatic Elastase - isolation & purification</subject><subject>Pancreatic Elastase - metabolism</subject><subject>serine proteinase</subject><subject>Solutions</subject><subject>Swine</subject><subject>triazine</subject><issn>0952-3499</issn><issn>1099-1352</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkE1vEzEQhi1ERUPhLyCfEEhsOt6xd-MUVapSCK1awkeh3EbejV1M96OsN7T593W0UblwwRdbo9fPO3oYOxAwFgDpvgCtE4EqfZUCgBD7In0tcJq9xRym06OT4-T0_IsScIhjGM8WB2miHrHRw6_HbARapQlKrXfZ0xB-RYrWCp6wXRGPhBxG7PzYBn_VvOFh3fQ_4ztw0yy5_WOqlel92_DW8cK3ta9t70tunPON79e88lcxGLhrO24rE3oTbHjGdpypgn2-vffYt_fvLmYfkrPF_GR2dJaUMi6RWCxKLJybZJnIlNYOVKq1lLnGcpLnRaGVlRoQsUBXqqWcuMKUqJWE0kkLuMdeDtybrv29sqGn2ofSVpVpbLsKlKcKMhQqBr8OwbJrQ-iso5vO16ZbkwDaWKaNL9r4osEyiThDyihaJoqWabBMSECzBaW0ob7Y1q-K2i7_MrdaY-D7ELj1lV3_X-c_K7eTCE4GsA-9vXsAm-6ashxzRZcf53R6Of_x6eIzRuY9ZHqktw</recordid><startdate>200011</startdate><enddate>200011</enddate><creator>Filippusson, Hörður</creator><creator>Erlendsson, Lýður S.</creator><creator>Lowe, Christopher R.</creator><general>John Wiley & Sons, Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>200011</creationdate><title>Design, synthesis and evaluation of biomimetic affinity ligands for elastases</title><author>Filippusson, Hörður ; Erlendsson, Lýður S. ; Lowe, Christopher R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4000-e3bc3bff86616599f0529944793c877bb95e490333b3fc5d48fbac39540cf4e03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>affinity chromatography</topic><topic>Animals</topic><topic>biomimetic ligands</topic><topic>Chromatography, Affinity</topic><topic>Drug Design</topic><topic>elastase</topic><topic>Fishes</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Molecular Mimicry</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - metabolism</topic><topic>Pancreatic Elastase - chemistry</topic><topic>Pancreatic Elastase - isolation & purification</topic><topic>Pancreatic Elastase - metabolism</topic><topic>serine proteinase</topic><topic>Solutions</topic><topic>Swine</topic><topic>triazine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Filippusson, Hörður</creatorcontrib><creatorcontrib>Erlendsson, Lýður S.</creatorcontrib><creatorcontrib>Lowe, Christopher R.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of molecular recognition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Filippusson, Hörður</au><au>Erlendsson, Lýður S.</au><au>Lowe, Christopher R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, synthesis and evaluation of biomimetic affinity ligands for elastases</atitle><jtitle>Journal of molecular recognition</jtitle><addtitle>J. Mol. Recognit</addtitle><date>2000-11</date><risdate>2000</risdate><volume>13</volume><issue>6</issue><spage>370</spage><epage>381</epage><pages>370-381</pages><issn>0952-3499</issn><eissn>1099-1352</eissn><abstract>A low‐molecular‐weight biomimetic affinity ligand selective for binding elastase has been designed and synthesized. The ligand was based on mimicking part of the interaction between a natural inhibitor, turkey ovomucoid inhibitor and elastase, and modelled from the X‐ray crystallographic structure of the enzyme–inhibitor complex. Limited solid‐phase combinatorial chemistry was used to synthesize 12 variants of the lead ligand using the triazine moiety as the scaffold for assembly. The ligand library was screened for its ability to bind elastase and trypsin, and two ligands were studied further. Ligand C4/6 [2‐alanyl‐alanyl‐4‐tryptamino‐6‐(α‐lysyl)‐s‐triazine] was found to bind porcine pancreatic elastase, but not trypsin, with a dissociation constant of 6 × 10−5 M and a binding capacity of 21 mg elastase per ml gel. The adsorbent was used to purify elastase from a crude extract of porcine pancreas. Immobilized ligand C4/5 6 [2‐alanyl‐alanyl‐4‐tyramino‐6‐(α‐lysyl)‐s‐triazine] was similarly chosen for optimal binding of elastase from cod and used to purify the enzyme from a crude extract of cod pyloric caeca. Ligand C4/6 was subsequently synthesized in solution and its structure verified by 1H‐NMR. Copyright © 2000 John Wiley & Sons, Ltd.
Abbreviations used:
BAPNA
benzoyl arginine P‐nitroanilide
HLE
human leucocyte elastase
PPE
porcine pancreatic elastase.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>11114070</pmid><doi>10.1002/1099-1352(200011/12)13:6<370::AID-JMR510>3.0.CO;2-5</doi><tpages>12</tpages></addata></record> |
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subjects | affinity chromatography Animals biomimetic ligands Chromatography, Affinity Drug Design elastase Fishes Ligands Models, Molecular Molecular Mimicry Oligopeptides - chemistry Oligopeptides - metabolism Pancreatic Elastase - chemistry Pancreatic Elastase - isolation & purification Pancreatic Elastase - metabolism serine proteinase Solutions Swine triazine |
title | Design, synthesis and evaluation of biomimetic affinity ligands for elastases |
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