A Hexasaccharide Containing Rare 2‐O‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II
Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2‐...
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| Veröffentlicht in: | Angewandte Chemie International Edition 2017-02, Vol.56 (9), p.2312-2317 |
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| creator | Sankaranarayanan, Nehru Viji Strebel, Tamara R. Boothello, Rio S. Sheerin, Kevin Raghuraman, Arjun Sallas, Florence Mosier, Philip D. Watermeyer, Nicholas D. Oscarson, Stefan Desai, Umesh R. |
| description | Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2‐O‐sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250‐fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG‐binding protein(s), which may lead to chemical biology or drug discovery tools.
A computational strategy was used to identify a rare sequence of glucuronic acid 2‐O‐sulfate residues in a library of heparan sulfate hexasaccharides. The designed sequence was found to activate heparin cofactor II 250‐fold, while leaving antithrombin, a closely related serpin, essentially unactivated. |
| doi_str_mv | 10.1002/anie.201609541 |
| format | Article |
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A computational strategy was used to identify a rare sequence of glucuronic acid 2‐O‐sulfate residues in a library of heparan sulfate hexasaccharides. The designed sequence was found to activate heparin cofactor II 250‐fold, while leaving antithrombin, a closely related serpin, essentially unactivated.</description><edition>International ed. in English</edition><identifier>ISSN: 1433-7851</identifier><identifier>EISSN: 1521-3773</identifier><identifier>DOI: 10.1002/anie.201609541</identifier><identifier>PMID: 28124818</identifier><identifier>CODEN: ACIEAY</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Acids ; Anticoagulants ; Antithrombin ; Blood plasma ; carbohydrates ; chemical biology ; Communication ; Communications ; Computation ; Computer applications ; Discovery tools ; Drug Discovery ; Glucuronates - chemistry ; Glucuronates - pharmacology ; glycosaminoglycans ; Heparan sulfate ; Heparin ; Heparin Cofactor II - agonists ; Heparin Cofactor II - metabolism ; Heparitin Sulfate - chemistry ; Heparitin Sulfate - pharmacology ; Humans ; in silico screening ; Protein Binding ; Residues ; serpins ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Sulfates</subject><ispartof>Angewandte Chemie International Edition, 2017-02, Vol.56 (9), p.2312-2317</ispartof><rights>2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.</rights><rights>2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><rights>2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5991-df0fe92e198bb0eb601f14d9e929ffdc4e7388d44c545c4ea2fe1a198f7065193</citedby><cites>FETCH-LOGICAL-c5991-df0fe92e198bb0eb601f14d9e929ffdc4e7388d44c545c4ea2fe1a198f7065193</cites><orcidid>0000-0002-1976-6597 ; 0000-0002-2870-9164</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fanie.201609541$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fanie.201609541$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28124818$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sankaranarayanan, Nehru Viji</creatorcontrib><creatorcontrib>Strebel, Tamara R.</creatorcontrib><creatorcontrib>Boothello, Rio S.</creatorcontrib><creatorcontrib>Sheerin, Kevin</creatorcontrib><creatorcontrib>Raghuraman, Arjun</creatorcontrib><creatorcontrib>Sallas, Florence</creatorcontrib><creatorcontrib>Mosier, Philip D.</creatorcontrib><creatorcontrib>Watermeyer, Nicholas D.</creatorcontrib><creatorcontrib>Oscarson, Stefan</creatorcontrib><creatorcontrib>Desai, Umesh R.</creatorcontrib><title>A Hexasaccharide Containing Rare 2‐O‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II</title><title>Angewandte Chemie International Edition</title><addtitle>Angew Chem Int Ed Engl</addtitle><description>Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2‐O‐sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250‐fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG‐binding protein(s), which may lead to chemical biology or drug discovery tools.
A computational strategy was used to identify a rare sequence of glucuronic acid 2‐O‐sulfate residues in a library of heparan sulfate hexasaccharides. The designed sequence was found to activate heparin cofactor II 250‐fold, while leaving antithrombin, a closely related serpin, essentially unactivated.</description><subject>Acids</subject><subject>Anticoagulants</subject><subject>Antithrombin</subject><subject>Blood plasma</subject><subject>carbohydrates</subject><subject>chemical biology</subject><subject>Communication</subject><subject>Communications</subject><subject>Computation</subject><subject>Computer applications</subject><subject>Discovery tools</subject><subject>Drug Discovery</subject><subject>Glucuronates - chemistry</subject><subject>Glucuronates - pharmacology</subject><subject>glycosaminoglycans</subject><subject>Heparan sulfate</subject><subject>Heparin</subject><subject>Heparin Cofactor II - agonists</subject><subject>Heparin Cofactor II - metabolism</subject><subject>Heparitin Sulfate - chemistry</subject><subject>Heparitin Sulfate - pharmacology</subject><subject>Humans</subject><subject>in silico screening</subject><subject>Protein Binding</subject><subject>Residues</subject><subject>serpins</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Sulfates</subject><issn>1433-7851</issn><issn>1521-3773</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><recordid>eNqFkc9uEzEQh1cIREvhyhGtxIVLgsfrXdsXpCgqbaSKSi2cLcc7bl1tvMHebcmNR-AZ-ySdKCX8OcDB8tj-_MnjX1G8BjYFxvh7GwNOOYOG6VrAk-IQag6TSsrqKdWiqiZS1XBQvMj5hnilWPO8OOAKuFCgDotxVp7iN5utc9c2hRbLeR8HG2KIV-WFTVjy--8_zmlcjp23A1J10o1uTH0Mrpy50JYXmEM7Yi4vsUM3hFvsNnRCBfGZ_GsyRxJ764Y-lYvFy-KZt13GV4_zUfHl4_Hn-enk7PxkMZ-dTVytNUxazzxqjqDVcslw2TDwIFpNe9r71gmUlVKtEK4WNa0s9wiWaC9ZU4OujooPO-96XK6wdRiHZDuzTmFl08b0Npg_T2K4Nlf9rakrQf-2Fbx7FKT-K7U4mFXIDrvORuzHbEA1nKtK6i369i_0ph9TpPYM6EZKWVeM_5NSjVSKNwKImu4ol_qcE_r9k4GZbe5mm7vZ504X3vze6B7_GTQBegfchQ43_9GZ2afF8S_5AyshvWQ</recordid><startdate>20170220</startdate><enddate>20170220</enddate><creator>Sankaranarayanan, Nehru Viji</creator><creator>Strebel, Tamara R.</creator><creator>Boothello, Rio S.</creator><creator>Sheerin, Kevin</creator><creator>Raghuraman, Arjun</creator><creator>Sallas, Florence</creator><creator>Mosier, Philip D.</creator><creator>Watermeyer, Nicholas D.</creator><creator>Oscarson, Stefan</creator><creator>Desai, Umesh R.</creator><general>Wiley Subscription Services, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</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>7TM</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1976-6597</orcidid><orcidid>https://orcid.org/0000-0002-2870-9164</orcidid></search><sort><creationdate>20170220</creationdate><title>A Hexasaccharide Containing Rare 2‐O‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II</title><author>Sankaranarayanan, Nehru Viji ; Strebel, Tamara R. ; Boothello, Rio S. ; Sheerin, Kevin ; Raghuraman, Arjun ; Sallas, Florence ; Mosier, Philip D. ; Watermeyer, Nicholas D. ; Oscarson, Stefan ; Desai, Umesh R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5991-df0fe92e198bb0eb601f14d9e929ffdc4e7388d44c545c4ea2fe1a198f7065193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Acids</topic><topic>Anticoagulants</topic><topic>Antithrombin</topic><topic>Blood plasma</topic><topic>carbohydrates</topic><topic>chemical biology</topic><topic>Communication</topic><topic>Communications</topic><topic>Computation</topic><topic>Computer applications</topic><topic>Discovery tools</topic><topic>Drug Discovery</topic><topic>Glucuronates - chemistry</topic><topic>Glucuronates - pharmacology</topic><topic>glycosaminoglycans</topic><topic>Heparan sulfate</topic><topic>Heparin</topic><topic>Heparin Cofactor II - agonists</topic><topic>Heparin Cofactor II - metabolism</topic><topic>Heparitin Sulfate - chemistry</topic><topic>Heparitin Sulfate - pharmacology</topic><topic>Humans</topic><topic>in silico screening</topic><topic>Protein Binding</topic><topic>Residues</topic><topic>serpins</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Sulfates</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sankaranarayanan, Nehru Viji</creatorcontrib><creatorcontrib>Strebel, Tamara R.</creatorcontrib><creatorcontrib>Boothello, Rio S.</creatorcontrib><creatorcontrib>Sheerin, Kevin</creatorcontrib><creatorcontrib>Raghuraman, Arjun</creatorcontrib><creatorcontrib>Sallas, Florence</creatorcontrib><creatorcontrib>Mosier, Philip D.</creatorcontrib><creatorcontrib>Watermeyer, Nicholas D.</creatorcontrib><creatorcontrib>Oscarson, Stefan</creatorcontrib><creatorcontrib>Desai, Umesh R.</creatorcontrib><collection>Wiley Online Library (Open Access Collection)</collection><collection>Wiley Free Content</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Angewandte Chemie International Edition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sankaranarayanan, Nehru Viji</au><au>Strebel, Tamara R.</au><au>Boothello, Rio S.</au><au>Sheerin, Kevin</au><au>Raghuraman, Arjun</au><au>Sallas, Florence</au><au>Mosier, Philip D.</au><au>Watermeyer, Nicholas D.</au><au>Oscarson, Stefan</au><au>Desai, Umesh R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Hexasaccharide Containing Rare 2‐O‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II</atitle><jtitle>Angewandte Chemie International Edition</jtitle><addtitle>Angew Chem Int Ed Engl</addtitle><date>2017-02-20</date><risdate>2017</risdate><volume>56</volume><issue>9</issue><spage>2312</spage><epage>2317</epage><pages>2312-2317</pages><issn>1433-7851</issn><eissn>1521-3773</eissn><coden>ACIEAY</coden><abstract>Glycosaminoglycan (GAG) sequences that selectively target heparin cofactor II (HCII), a key serpin present in human plasma, remain unknown. Using a computational strategy on a library of 46 656 heparan sulfate hexasaccharides we identified a rare sequence consisting of consecutive glucuronic acid 2‐O‐sulfate residues as selectively targeting HCII. This and four other unique hexasaccharides were chemically synthesized. The designed sequence was found to activate HCII ca. 250‐fold, while leaving aside antithrombin, a closely related serpin, essentially unactivated. This group of rare designed hexasaccharides will help understand HCII function. More importantly, our results show for the first time that rigorous use of computational techniques can lead to discovery of unique GAG sequences that can selectively target GAG‐binding protein(s), which may lead to chemical biology or drug discovery tools.
A computational strategy was used to identify a rare sequence of glucuronic acid 2‐O‐sulfate residues in a library of heparan sulfate hexasaccharides. The designed sequence was found to activate heparin cofactor II 250‐fold, while leaving antithrombin, a closely related serpin, essentially unactivated.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28124818</pmid><doi>10.1002/anie.201609541</doi><tpages>6</tpages><edition>International ed. in English</edition><orcidid>https://orcid.org/0000-0002-1976-6597</orcidid><orcidid>https://orcid.org/0000-0002-2870-9164</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acids Anticoagulants Antithrombin Blood plasma carbohydrates chemical biology Communication Communications Computation Computer applications Discovery tools Drug Discovery Glucuronates - chemistry Glucuronates - pharmacology glycosaminoglycans Heparan sulfate Heparin Heparin Cofactor II - agonists Heparin Cofactor II - metabolism Heparitin Sulfate - chemistry Heparitin Sulfate - pharmacology Humans in silico screening Protein Binding Residues serpins Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Sulfates |
| title | A Hexasaccharide Containing Rare 2‐O‐Sulfate‐Glucuronic Acid Residues Selectively Activates Heparin Cofactor II |
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