Identification of Peptidic Antagonists of Vascular Endothelial Growth Factor Receptor 1 by Scanning the Binding Epitopes of Its Ligands
Cancer angiogenesis is mainly initiated by vascular endothelial growth factors (VEGFs). On the basis of the reported crystal structures of three natural ligands (VEGF-A, -B, and PlGF) with the major receptors VEGFR-1 and VEGFR-2, we scanned receptor-binding epitopes of these ligands by designing lin...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-08, Vol.60 (15), p.6598-6606 |
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| container_title | Journal of medicinal chemistry |
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| creator | Wang, Lei Zhou, Lingyu Reille-Seroussi, Marie Gagey-Eilstein, Nathalie Broussy, Sylvain Zhang, Tianyu Ji, Lili Vidal, Michel Liu, Wang-Qing |
| description | Cancer angiogenesis is mainly initiated by vascular endothelial growth factors (VEGFs). On the basis of the reported crystal structures of three natural ligands (VEGF-A, -B, and PlGF) with the major receptors VEGFR-1 and VEGFR-2, we scanned receptor-binding epitopes of these ligands by designing linear and cyclic peptides with the aim to disrupt the VEGF-A/VEGFR-1 interaction, which is implicated in cancer development. The ability of peptides to inhibit this interaction was evaluated by an ELISA-based assay. Several peptides, especially those mimicking loop 1 (L1) of these ligands that binds primarily to domain D3 of VEGFRs, have demonstrated higher inhibition for VEGF-A/VEGFR-1 binding. They have also shown inhibitory effects on VEGF-induced tube formation in HUVECs (human umbilical vein endothelial cells). These results validate the domain D3 of VEGFRs as an efficient target for the design of VEGFR antagonists. |
| doi_str_mv | 10.1021/acs.jmedchem.7b00283 |
| format | Article |
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On the basis of the reported crystal structures of three natural ligands (VEGF-A, -B, and PlGF) with the major receptors VEGFR-1 and VEGFR-2, we scanned receptor-binding epitopes of these ligands by designing linear and cyclic peptides with the aim to disrupt the VEGF-A/VEGFR-1 interaction, which is implicated in cancer development. The ability of peptides to inhibit this interaction was evaluated by an ELISA-based assay. Several peptides, especially those mimicking loop 1 (L1) of these ligands that binds primarily to domain D3 of VEGFRs, have demonstrated higher inhibition for VEGF-A/VEGFR-1 binding. They have also shown inhibitory effects on VEGF-induced tube formation in HUVECs (human umbilical vein endothelial cells). These results validate the domain D3 of VEGFRs as an efficient target for the design of VEGFR antagonists.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.7b00283</identifier><identifier>PMID: 28686443</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Angiogenesis Inhibitors - chemistry ; Angiogenesis Inhibitors - pharmacology ; Drug Design ; Epitopes - chemistry ; Human Umbilical Vein Endothelial Cells ; Humans ; Ligands ; Membrane Proteins - chemistry ; Peptide Fragments - chemistry ; Peptide Fragments - pharmacology ; Peptides - chemistry ; Peptides - pharmacology ; Peptides, Cyclic - chemistry ; Peptides, Cyclic - pharmacology ; Protein Domains ; Vascular Endothelial Growth Factor A - chemistry ; Vascular Endothelial Growth Factor B - chemistry ; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-1 - chemistry</subject><ispartof>Journal of medicinal chemistry, 2017-08, Vol.60 (15), p.6598-6606</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-974525e88888615900b5c3840009d40cbbf4c69b3d4f388ce2532f5a12aab4d63</citedby><cites>FETCH-LOGICAL-a348t-974525e88888615900b5c3840009d40cbbf4c69b3d4f388ce2532f5a12aab4d63</cites><orcidid>0000-0003-0511-3058</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b00283$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00283$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28686443$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Zhou, Lingyu</creatorcontrib><creatorcontrib>Reille-Seroussi, Marie</creatorcontrib><creatorcontrib>Gagey-Eilstein, Nathalie</creatorcontrib><creatorcontrib>Broussy, Sylvain</creatorcontrib><creatorcontrib>Zhang, Tianyu</creatorcontrib><creatorcontrib>Ji, Lili</creatorcontrib><creatorcontrib>Vidal, Michel</creatorcontrib><creatorcontrib>Liu, Wang-Qing</creatorcontrib><title>Identification of Peptidic Antagonists of Vascular Endothelial Growth Factor Receptor 1 by Scanning the Binding Epitopes of Its Ligands</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Cancer angiogenesis is mainly initiated by vascular endothelial growth factors (VEGFs). On the basis of the reported crystal structures of three natural ligands (VEGF-A, -B, and PlGF) with the major receptors VEGFR-1 and VEGFR-2, we scanned receptor-binding epitopes of these ligands by designing linear and cyclic peptides with the aim to disrupt the VEGF-A/VEGFR-1 interaction, which is implicated in cancer development. The ability of peptides to inhibit this interaction was evaluated by an ELISA-based assay. Several peptides, especially those mimicking loop 1 (L1) of these ligands that binds primarily to domain D3 of VEGFRs, have demonstrated higher inhibition for VEGF-A/VEGFR-1 binding. They have also shown inhibitory effects on VEGF-induced tube formation in HUVECs (human umbilical vein endothelial cells). These results validate the domain D3 of VEGFRs as an efficient target for the design of VEGFR antagonists.</description><subject>Angiogenesis Inhibitors - chemistry</subject><subject>Angiogenesis Inhibitors - pharmacology</subject><subject>Drug Design</subject><subject>Epitopes - chemistry</subject><subject>Human Umbilical Vein Endothelial Cells</subject><subject>Humans</subject><subject>Ligands</subject><subject>Membrane Proteins - chemistry</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptide Fragments - pharmacology</subject><subject>Peptides - chemistry</subject><subject>Peptides - pharmacology</subject><subject>Peptides, Cyclic - chemistry</subject><subject>Peptides, Cyclic - pharmacology</subject><subject>Protein Domains</subject><subject>Vascular Endothelial Growth Factor A - chemistry</subject><subject>Vascular Endothelial Growth Factor B - chemistry</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - chemistry</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1OAyEUhYnRaK2-gTEs3Uzlb6bMUptWmzTR-LedMMC0mCmMwMT0CXxtqa0uZcPN5Tvn5nIAuMBohBHB10KG0ftaK7nS69G4RohwegAGOCcoYxyxQzBIPZKRgtATcBrCO0KIYkKPwQnhBS8YowPwNVfaRtMYKaJxFroGPuouGmUkvLFRLJ01IYZt_00E2bfCw6lVLq50a0QL77z7jCs4EzI6D5-0TOJUYFhv4LMU1hq7hAmGt8aqbT3tTHSd_nGcJ-OFWQqrwhk4akQb9Pn-HoLX2fRlcp8tHu7mk5tFJijjMSvHLCe55ttT4LxEqM4l5SytViqGZF03TBZlTRVrKOdSk5ySJheYCFEzVdAhuNr5dt599DrEam2C1G0rrHZ9qHCJx7TAJCcJZTtUeheC103VebMWflNhVG0jqFIE1W8E1T6CJLvcT-jr9PYn-v3zBKAd8CN3vbdp4f89vwHnspZ9</recordid><startdate>20170810</startdate><enddate>20170810</enddate><creator>Wang, Lei</creator><creator>Zhou, Lingyu</creator><creator>Reille-Seroussi, Marie</creator><creator>Gagey-Eilstein, Nathalie</creator><creator>Broussy, Sylvain</creator><creator>Zhang, Tianyu</creator><creator>Ji, Lili</creator><creator>Vidal, Michel</creator><creator>Liu, Wang-Qing</creator><general>American Chemical Society</general><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><orcidid>https://orcid.org/0000-0003-0511-3058</orcidid></search><sort><creationdate>20170810</creationdate><title>Identification of Peptidic Antagonists of Vascular Endothelial Growth Factor Receptor 1 by Scanning the Binding Epitopes of Its Ligands</title><author>Wang, Lei ; Zhou, Lingyu ; Reille-Seroussi, Marie ; Gagey-Eilstein, Nathalie ; Broussy, Sylvain ; Zhang, Tianyu ; Ji, Lili ; Vidal, Michel ; Liu, Wang-Qing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-974525e88888615900b5c3840009d40cbbf4c69b3d4f388ce2532f5a12aab4d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Angiogenesis Inhibitors - chemistry</topic><topic>Angiogenesis Inhibitors - pharmacology</topic><topic>Drug Design</topic><topic>Epitopes - chemistry</topic><topic>Human Umbilical Vein Endothelial Cells</topic><topic>Humans</topic><topic>Ligands</topic><topic>Membrane Proteins - chemistry</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptide Fragments - pharmacology</topic><topic>Peptides - chemistry</topic><topic>Peptides - pharmacology</topic><topic>Peptides, Cyclic - chemistry</topic><topic>Peptides, Cyclic - pharmacology</topic><topic>Protein Domains</topic><topic>Vascular Endothelial Growth Factor A - chemistry</topic><topic>Vascular Endothelial Growth Factor B - chemistry</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - chemistry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Lei</creatorcontrib><creatorcontrib>Zhou, Lingyu</creatorcontrib><creatorcontrib>Reille-Seroussi, Marie</creatorcontrib><creatorcontrib>Gagey-Eilstein, Nathalie</creatorcontrib><creatorcontrib>Broussy, Sylvain</creatorcontrib><creatorcontrib>Zhang, Tianyu</creatorcontrib><creatorcontrib>Ji, Lili</creatorcontrib><creatorcontrib>Vidal, Michel</creatorcontrib><creatorcontrib>Liu, Wang-Qing</creatorcontrib><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 medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Lei</au><au>Zhou, Lingyu</au><au>Reille-Seroussi, Marie</au><au>Gagey-Eilstein, Nathalie</au><au>Broussy, Sylvain</au><au>Zhang, Tianyu</au><au>Ji, Lili</au><au>Vidal, Michel</au><au>Liu, Wang-Qing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Peptidic Antagonists of Vascular Endothelial Growth Factor Receptor 1 by Scanning the Binding Epitopes of Its Ligands</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-08-10</date><risdate>2017</risdate><volume>60</volume><issue>15</issue><spage>6598</spage><epage>6606</epage><pages>6598-6606</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Cancer angiogenesis is mainly initiated by vascular endothelial growth factors (VEGFs). On the basis of the reported crystal structures of three natural ligands (VEGF-A, -B, and PlGF) with the major receptors VEGFR-1 and VEGFR-2, we scanned receptor-binding epitopes of these ligands by designing linear and cyclic peptides with the aim to disrupt the VEGF-A/VEGFR-1 interaction, which is implicated in cancer development. The ability of peptides to inhibit this interaction was evaluated by an ELISA-based assay. Several peptides, especially those mimicking loop 1 (L1) of these ligands that binds primarily to domain D3 of VEGFRs, have demonstrated higher inhibition for VEGF-A/VEGFR-1 binding. 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| subjects | Angiogenesis Inhibitors - chemistry Angiogenesis Inhibitors - pharmacology Drug Design Epitopes - chemistry Human Umbilical Vein Endothelial Cells Humans Ligands Membrane Proteins - chemistry Peptide Fragments - chemistry Peptide Fragments - pharmacology Peptides - chemistry Peptides - pharmacology Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Protein Domains Vascular Endothelial Growth Factor A - chemistry Vascular Endothelial Growth Factor B - chemistry Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-1 - chemistry |
| title | Identification of Peptidic Antagonists of Vascular Endothelial Growth Factor Receptor 1 by Scanning the Binding Epitopes of Its Ligands |
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