Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain
The tandem BRCT domains (tBRCT) of BRCA1 engage phosphoserine‐containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, the first small‐molecule inhibitor of the BRCA1 tBR...
Gespeichert in:
Veröffentlicht in: | ChemMedChem 2019-09, Vol.14 (18), p.1620-1632 |
---|---|
Hauptverfasser: | , , , , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 1632 |
---|---|
container_issue | 18 |
container_start_page | 1620 |
container_title | ChemMedChem |
container_volume | 14 |
creator | Kurdekar, Vadiraj Giridharan, Saranya Subbarao, Jasti Nijaguna, Mamatha B. Periasamy, Jayaprakash Boggaram, Sanjana Shivange, Amol V. Sadasivam, Gayathri Padigaru, Muralidhara Potluri, Vijay Venkitaraman, Ashok R. Bharatham, Kavitha |
description | The tandem BRCT domains (tBRCT) of BRCA1 engage phosphoserine‐containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, the first small‐molecule inhibitor of the BRCA1 tBRCT domain, which selectively interrupts BRCA1‐mediated cellular responses evoked by DNA damage. Here, we combine structure‐guided chemical elaboration, protein mutagenesis and cellular assays to define the structural features responsible for Bractoppin's activity. Bractoppin fails to bind mutant forms of BRCA1 tBRCT bearing K1702A, a key residue mediating phosphopeptide recognition, or F1662R or L1701K that adjoin the pSer‐recognition site. However, the M1775R mutation, which engages the Phe residue in the consensus phosphopeptide motif pSer‐X‐X‐Phe, does not affect Bractoppin binding, confirming a binding mode distinct from the substrate phosphopeptide binding. We explored these structural features through structure‐guided chemical elaboration and characterized structure–activity relationships (SARs) in biochemical assays. Two analogues, CCBT2088 and CCBT2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the activity of a novel inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target protein–protein interactions.
Taming BRCA1 by its tail, tBRCT: Bractoppin blocks the phosphopeptide‐binding site of BRCA1 via structural features distinct from the substrate phosphopeptide. Chemical elaboration conceptualized from mutagenesis and structure‐guided strategies reveal structural features underlying the biochemical potency of Bractoppin analogs against BRCA1 tBRCT domain. This expands the scope of developing inhibitors targeting protein–protein interactions. |
doi_str_mv | 10.1002/cmdc.201900300 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2291336176</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2291336176</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3730-6aba0c0a3e4a715f82462c7386a05f1a57f7db77937250c65dfb0947e3acdf243</originalsourceid><addsrcrecordid>eNqFkLFOwzAQQC0EoqWwMiJLzC3nOImTEdIClUAgWubIcRxqlMTFdkDdWNmQ-EO-hEQtZWS6G969kx5CxwRGBMA7E1UuRh6QGIAC7KA-iUIYMhKx3e3O4h46sPYZwPcjEu2jHiWU-jEJ-uhj5kwjXGPk9_vnVaNymePZqnYLaZXFvM7x5JWXDXdK11gXeFbxsmzRW11K0ZQST-uFypTTxuI5N0_SqfoJ3xvtpKq_3782W4s5abjoNLbzXDwk5wS7dszxWFdc1Ydor-CllUebOUCPl5N5cj28ubuaJuc3Q0EZhWHIMw4COJU-ZyQoIs8PPcFoFHIICsIDVrA8YyymzAtAhEFeZBD7TFIu8sLz6QCdrr1Lo18aaV36rBtTty9Tz4vbMCFhYUuN1pQw2loji3RpVMXNKiWQduXTrny6Ld8enGy0TVbJfIv_pm6BeA28qVKu_tGlye04-ZP_APb6k5A</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2291336176</pqid></control><display><type>article</type><title>Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain</title><source>Wiley Online Library Journals Frontfile Complete</source><creator>Kurdekar, Vadiraj ; Giridharan, Saranya ; Subbarao, Jasti ; Nijaguna, Mamatha B. ; Periasamy, Jayaprakash ; Boggaram, Sanjana ; Shivange, Amol V. ; Sadasivam, Gayathri ; Padigaru, Muralidhara ; Potluri, Vijay ; Venkitaraman, Ashok R. ; Bharatham, Kavitha</creator><creatorcontrib>Kurdekar, Vadiraj ; Giridharan, Saranya ; Subbarao, Jasti ; Nijaguna, Mamatha B. ; Periasamy, Jayaprakash ; Boggaram, Sanjana ; Shivange, Amol V. ; Sadasivam, Gayathri ; Padigaru, Muralidhara ; Potluri, Vijay ; Venkitaraman, Ashok R. ; Bharatham, Kavitha</creatorcontrib><description>The tandem BRCT domains (tBRCT) of BRCA1 engage phosphoserine‐containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, the first small‐molecule inhibitor of the BRCA1 tBRCT domain, which selectively interrupts BRCA1‐mediated cellular responses evoked by DNA damage. Here, we combine structure‐guided chemical elaboration, protein mutagenesis and cellular assays to define the structural features responsible for Bractoppin's activity. Bractoppin fails to bind mutant forms of BRCA1 tBRCT bearing K1702A, a key residue mediating phosphopeptide recognition, or F1662R or L1701K that adjoin the pSer‐recognition site. However, the M1775R mutation, which engages the Phe residue in the consensus phosphopeptide motif pSer‐X‐X‐Phe, does not affect Bractoppin binding, confirming a binding mode distinct from the substrate phosphopeptide binding. We explored these structural features through structure‐guided chemical elaboration and characterized structure–activity relationships (SARs) in biochemical assays. Two analogues, CCBT2088 and CCBT2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the activity of a novel inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target protein–protein interactions.
Taming BRCA1 by its tail, tBRCT: Bractoppin blocks the phosphopeptide‐binding site of BRCA1 via structural features distinct from the substrate phosphopeptide. Chemical elaboration conceptualized from mutagenesis and structure‐guided strategies reveal structural features underlying the biochemical potency of Bractoppin analogs against BRCA1 tBRCT domain. This expands the scope of developing inhibitors targeting protein–protein interactions.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201900300</identifier><identifier>PMID: 31334915</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Binding ; BRCA1 ; BRCA1 protein ; BRCT domain ; Breast cancer ; Cell cycle ; Cellular structure ; Chemical synthesis ; Deoxyribonucleic acid ; DNA ; DNA damage ; DNA repair ; GIST ; Homologous recombination ; Inhibitors ; Irradiation ; Mutagenesis ; Mutation ; Organic chemistry ; Phosphoserine ; Protein interaction ; Protein structure ; Proteins ; Protein–protein interactions ; Structural damage ; Substrates</subject><ispartof>ChemMedChem, 2019-09, Vol.14 (18), p.1620-1632</ispartof><rights>2019 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3730-6aba0c0a3e4a715f82462c7386a05f1a57f7db77937250c65dfb0947e3acdf243</citedby><cites>FETCH-LOGICAL-c3730-6aba0c0a3e4a715f82462c7386a05f1a57f7db77937250c65dfb0947e3acdf243</cites><orcidid>0000-0002-2610-7768</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%2Fcmdc.201900300$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201900300$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31334915$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kurdekar, Vadiraj</creatorcontrib><creatorcontrib>Giridharan, Saranya</creatorcontrib><creatorcontrib>Subbarao, Jasti</creatorcontrib><creatorcontrib>Nijaguna, Mamatha B.</creatorcontrib><creatorcontrib>Periasamy, Jayaprakash</creatorcontrib><creatorcontrib>Boggaram, Sanjana</creatorcontrib><creatorcontrib>Shivange, Amol V.</creatorcontrib><creatorcontrib>Sadasivam, Gayathri</creatorcontrib><creatorcontrib>Padigaru, Muralidhara</creatorcontrib><creatorcontrib>Potluri, Vijay</creatorcontrib><creatorcontrib>Venkitaraman, Ashok R.</creatorcontrib><creatorcontrib>Bharatham, Kavitha</creatorcontrib><title>Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>The tandem BRCT domains (tBRCT) of BRCA1 engage phosphoserine‐containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, the first small‐molecule inhibitor of the BRCA1 tBRCT domain, which selectively interrupts BRCA1‐mediated cellular responses evoked by DNA damage. Here, we combine structure‐guided chemical elaboration, protein mutagenesis and cellular assays to define the structural features responsible for Bractoppin's activity. Bractoppin fails to bind mutant forms of BRCA1 tBRCT bearing K1702A, a key residue mediating phosphopeptide recognition, or F1662R or L1701K that adjoin the pSer‐recognition site. However, the M1775R mutation, which engages the Phe residue in the consensus phosphopeptide motif pSer‐X‐X‐Phe, does not affect Bractoppin binding, confirming a binding mode distinct from the substrate phosphopeptide binding. We explored these structural features through structure‐guided chemical elaboration and characterized structure–activity relationships (SARs) in biochemical assays. Two analogues, CCBT2088 and CCBT2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the activity of a novel inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target protein–protein interactions.
Taming BRCA1 by its tail, tBRCT: Bractoppin blocks the phosphopeptide‐binding site of BRCA1 via structural features distinct from the substrate phosphopeptide. Chemical elaboration conceptualized from mutagenesis and structure‐guided strategies reveal structural features underlying the biochemical potency of Bractoppin analogs against BRCA1 tBRCT domain. This expands the scope of developing inhibitors targeting protein–protein interactions.</description><subject>Binding</subject><subject>BRCA1</subject><subject>BRCA1 protein</subject><subject>BRCT domain</subject><subject>Breast cancer</subject><subject>Cell cycle</subject><subject>Cellular structure</subject><subject>Chemical synthesis</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>GIST</subject><subject>Homologous recombination</subject><subject>Inhibitors</subject><subject>Irradiation</subject><subject>Mutagenesis</subject><subject>Mutation</subject><subject>Organic chemistry</subject><subject>Phosphoserine</subject><subject>Protein interaction</subject><subject>Protein structure</subject><subject>Proteins</subject><subject>Protein–protein interactions</subject><subject>Structural damage</subject><subject>Substrates</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNqFkLFOwzAQQC0EoqWwMiJLzC3nOImTEdIClUAgWubIcRxqlMTFdkDdWNmQ-EO-hEQtZWS6G969kx5CxwRGBMA7E1UuRh6QGIAC7KA-iUIYMhKx3e3O4h46sPYZwPcjEu2jHiWU-jEJ-uhj5kwjXGPk9_vnVaNymePZqnYLaZXFvM7x5JWXDXdK11gXeFbxsmzRW11K0ZQST-uFypTTxuI5N0_SqfoJ3xvtpKq_3782W4s5abjoNLbzXDwk5wS7dszxWFdc1Ydor-CllUebOUCPl5N5cj28ubuaJuc3Q0EZhWHIMw4COJU-ZyQoIs8PPcFoFHIICsIDVrA8YyymzAtAhEFeZBD7TFIu8sLz6QCdrr1Lo18aaV36rBtTty9Tz4vbMCFhYUuN1pQw2loji3RpVMXNKiWQduXTrny6Ld8enGy0TVbJfIv_pm6BeA28qVKu_tGlye04-ZP_APb6k5A</recordid><startdate>20190918</startdate><enddate>20190918</enddate><creator>Kurdekar, Vadiraj</creator><creator>Giridharan, Saranya</creator><creator>Subbarao, Jasti</creator><creator>Nijaguna, Mamatha B.</creator><creator>Periasamy, Jayaprakash</creator><creator>Boggaram, Sanjana</creator><creator>Shivange, Amol V.</creator><creator>Sadasivam, Gayathri</creator><creator>Padigaru, Muralidhara</creator><creator>Potluri, Vijay</creator><creator>Venkitaraman, Ashok R.</creator><creator>Bharatham, Kavitha</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0002-2610-7768</orcidid></search><sort><creationdate>20190918</creationdate><title>Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain</title><author>Kurdekar, Vadiraj ; Giridharan, Saranya ; Subbarao, Jasti ; Nijaguna, Mamatha B. ; Periasamy, Jayaprakash ; Boggaram, Sanjana ; Shivange, Amol V. ; Sadasivam, Gayathri ; Padigaru, Muralidhara ; Potluri, Vijay ; Venkitaraman, Ashok R. ; Bharatham, Kavitha</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3730-6aba0c0a3e4a715f82462c7386a05f1a57f7db77937250c65dfb0947e3acdf243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Binding</topic><topic>BRCA1</topic><topic>BRCA1 protein</topic><topic>BRCT domain</topic><topic>Breast cancer</topic><topic>Cell cycle</topic><topic>Cellular structure</topic><topic>Chemical synthesis</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA repair</topic><topic>GIST</topic><topic>Homologous recombination</topic><topic>Inhibitors</topic><topic>Irradiation</topic><topic>Mutagenesis</topic><topic>Mutation</topic><topic>Organic chemistry</topic><topic>Phosphoserine</topic><topic>Protein interaction</topic><topic>Protein structure</topic><topic>Proteins</topic><topic>Protein–protein interactions</topic><topic>Structural damage</topic><topic>Substrates</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kurdekar, Vadiraj</creatorcontrib><creatorcontrib>Giridharan, Saranya</creatorcontrib><creatorcontrib>Subbarao, Jasti</creatorcontrib><creatorcontrib>Nijaguna, Mamatha B.</creatorcontrib><creatorcontrib>Periasamy, Jayaprakash</creatorcontrib><creatorcontrib>Boggaram, Sanjana</creatorcontrib><creatorcontrib>Shivange, Amol V.</creatorcontrib><creatorcontrib>Sadasivam, Gayathri</creatorcontrib><creatorcontrib>Padigaru, Muralidhara</creatorcontrib><creatorcontrib>Potluri, Vijay</creatorcontrib><creatorcontrib>Venkitaraman, Ashok R.</creatorcontrib><creatorcontrib>Bharatham, Kavitha</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kurdekar, Vadiraj</au><au>Giridharan, Saranya</au><au>Subbarao, Jasti</au><au>Nijaguna, Mamatha B.</au><au>Periasamy, Jayaprakash</au><au>Boggaram, Sanjana</au><au>Shivange, Amol V.</au><au>Sadasivam, Gayathri</au><au>Padigaru, Muralidhara</au><au>Potluri, Vijay</au><au>Venkitaraman, Ashok R.</au><au>Bharatham, Kavitha</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2019-09-18</date><risdate>2019</risdate><volume>14</volume><issue>18</issue><spage>1620</spage><epage>1632</epage><pages>1620-1632</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>The tandem BRCT domains (tBRCT) of BRCA1 engage phosphoserine‐containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, the first small‐molecule inhibitor of the BRCA1 tBRCT domain, which selectively interrupts BRCA1‐mediated cellular responses evoked by DNA damage. Here, we combine structure‐guided chemical elaboration, protein mutagenesis and cellular assays to define the structural features responsible for Bractoppin's activity. Bractoppin fails to bind mutant forms of BRCA1 tBRCT bearing K1702A, a key residue mediating phosphopeptide recognition, or F1662R or L1701K that adjoin the pSer‐recognition site. However, the M1775R mutation, which engages the Phe residue in the consensus phosphopeptide motif pSer‐X‐X‐Phe, does not affect Bractoppin binding, confirming a binding mode distinct from the substrate phosphopeptide binding. We explored these structural features through structure‐guided chemical elaboration and characterized structure–activity relationships (SARs) in biochemical assays. Two analogues, CCBT2088 and CCBT2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the activity of a novel inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target protein–protein interactions.
Taming BRCA1 by its tail, tBRCT: Bractoppin blocks the phosphopeptide‐binding site of BRCA1 via structural features distinct from the substrate phosphopeptide. Chemical elaboration conceptualized from mutagenesis and structure‐guided strategies reveal structural features underlying the biochemical potency of Bractoppin analogs against BRCA1 tBRCT domain. This expands the scope of developing inhibitors targeting protein–protein interactions.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>31334915</pmid><doi>10.1002/cmdc.201900300</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-2610-7768</orcidid></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1860-7179 |
ispartof | ChemMedChem, 2019-09, Vol.14 (18), p.1620-1632 |
issn | 1860-7179 1860-7187 |
language | eng |
recordid | cdi_proquest_journals_2291336176 |
source | Wiley Online Library Journals Frontfile Complete |
subjects | Binding BRCA1 BRCA1 protein BRCT domain Breast cancer Cell cycle Cellular structure Chemical synthesis Deoxyribonucleic acid DNA DNA damage DNA repair GIST Homologous recombination Inhibitors Irradiation Mutagenesis Mutation Organic chemistry Phosphoserine Protein interaction Protein structure Proteins Protein–protein interactions Structural damage Substrates |
title | Structure‐Guided Synthesis and Evaluation of Small‐Molecule Inhibitors Targeting Protein–Protein Interactions of BRCA1 tBRCT Domain |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-29T09%3A03%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Structure%E2%80%90Guided%20Synthesis%20and%20Evaluation%20of%20Small%E2%80%90Molecule%20Inhibitors%20Targeting%20Protein%E2%80%93Protein%20Interactions%20of%20BRCA1%20tBRCT%20Domain&rft.jtitle=ChemMedChem&rft.au=Kurdekar,%20Vadiraj&rft.date=2019-09-18&rft.volume=14&rft.issue=18&rft.spage=1620&rft.epage=1632&rft.pages=1620-1632&rft.issn=1860-7179&rft.eissn=1860-7187&rft_id=info:doi/10.1002/cmdc.201900300&rft_dat=%3Cproquest_cross%3E2291336176%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2291336176&rft_id=info:pmid/31334915&rfr_iscdi=true |