Aminopeptidase resistant Arg-Gly-Asp analogs are stable in plasma and inhibit platelet aggregation
Tetrapeptides containing the sequence Arg‐Gly‐Asp (RGD) antagonize fibrinogen binding to its platelet receptor (gp IIb/IIIa, integrin α11bβ3) and inhibit platelet aggregation in vitro. The peptides RGDS and RGDY(Me)‐NH2 were rapidly degraded when incubated in human, rat, and dog plasma. HPLC analysi...
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| Veröffentlicht in: | International Journal of Peptide and Protein Research 1991-08, Vol.38 (2), p.124-130 |
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| container_title | International Journal of Peptide and Protein Research |
| container_volume | 38 |
| creator | FOK, K.AM F. PANZER-KNODLE, SUSAN G. NICHOLSON, NANCY S. TJOENG, FOE S. FEIGEN, LARRY P. ADAMS, STEVEN P. |
| description | Tetrapeptides containing the sequence Arg‐Gly‐Asp (RGD) antagonize fibrinogen binding to its platelet receptor (gp IIb/IIIa, integrin α11bβ3) and inhibit platelet aggregation in vitro. The peptides RGDS and RGDY(Me)‐NH2 were rapidly degraded when incubated in human, rat, and dog plasma. HPLC analysis indicated that amino acids were sequentially removed from the peptide N‐terminus, and this degradation was prevented by the aminopeptidase inhibitor bestatin. Analogs of RGDY(Me)‐NH2 with an acetylated or deleted α‐amino group were prepared. Both analogs were stable when incubated in plasma, blocked 125I‐fibrinogen binding to activated platelets (IC50= 10–30μm) and inhibited ADP induced platelet aggregation (IC50= 10–30μm). This study concludes that aminopeptidase rapidly degrades RGD peptides in plasma, an important issue for in vivo testing of RGD peptides and analogs. RGD analogs intrinsically stabilized against aminopeptidase are stable in plasma and are important tools for antithrombotic studies involving antagonism of gp IIb/IIIa. |
| doi_str_mv | 10.1111/j.1399-3011.1991.tb01419.x |
| format | Article |
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The peptides RGDS and RGDY(Me)‐NH2 were rapidly degraded when incubated in human, rat, and dog plasma. HPLC analysis indicated that amino acids were sequentially removed from the peptide N‐terminus, and this degradation was prevented by the aminopeptidase inhibitor bestatin. Analogs of RGDY(Me)‐NH2 with an acetylated or deleted α‐amino group were prepared. Both analogs were stable when incubated in plasma, blocked 125I‐fibrinogen binding to activated platelets (IC50= 10–30μm) and inhibited ADP induced platelet aggregation (IC50= 10–30μm). This study concludes that aminopeptidase rapidly degrades RGD peptides in plasma, an important issue for in vivo testing of RGD peptides and analogs. RGD analogs intrinsically stabilized against aminopeptidase are stable in plasma and are important tools for antithrombotic studies involving antagonism of gp IIb/IIIa.</description><identifier>ISSN: 0367-8377</identifier><identifier>EISSN: 1399-3011</identifier><identifier>DOI: 10.1111/j.1399-3011.1991.tb01419.x</identifier><identifier>PMID: 1783488</identifier><identifier>CODEN: IJPPC3</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>aggregation ; Amino Acid Sequence ; aminopeptidase ; aminopeptidase: antagonist ; Aminopeptidases - pharmacology ; Binding Sites - drug effects ; Biological and medical sciences ; Blood. Blood coagulation. Reticuloendothelial system ; Dose-Response Relationship, Drug ; fibrinogen ; Fibrinogen - antagonists & inhibitors ; gp IIb/IIIa ; integrin α11bβ3 platelet ; Integrins - antagonists & inhibitors ; Medical sciences ; Molecular Sequence Data ; Pharmacology. Drug treatments ; Platelet Aggregation - drug effects ; Platelet Aggregation Inhibitors - metabolism ; Platelet Aggregation Inhibitors - pharmacology ; Platelet Membrane Glycoproteins - antagonists & inhibitors ; platelets ; Receptors, Immunologic ; Receptors, Peptide ; RGD analogs</subject><ispartof>International Journal of Peptide and Protein Research, 1991-08, Vol.38 (2), p.124-130</ispartof><rights>1992 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4684-cbf88c50bfed0672ac11ac47c82a0aa157060cd8c4e199a4ef44d3fca11c989c3</citedby><cites>FETCH-LOGICAL-c4684-cbf88c50bfed0672ac11ac47c82a0aa157060cd8c4e199a4ef44d3fca11c989c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1399-3011.1991.tb01419.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1399-3011.1991.tb01419.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4960782$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1783488$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>FOK, K.AM F.</creatorcontrib><creatorcontrib>PANZER-KNODLE, SUSAN G.</creatorcontrib><creatorcontrib>NICHOLSON, NANCY S.</creatorcontrib><creatorcontrib>TJOENG, FOE S.</creatorcontrib><creatorcontrib>FEIGEN, LARRY P.</creatorcontrib><creatorcontrib>ADAMS, STEVEN P.</creatorcontrib><title>Aminopeptidase resistant Arg-Gly-Asp analogs are stable in plasma and inhibit platelet aggregation</title><title>International Journal of Peptide and Protein Research</title><addtitle>Int J Pept Protein Res</addtitle><description>Tetrapeptides containing the sequence Arg‐Gly‐Asp (RGD) antagonize fibrinogen binding to its platelet receptor (gp IIb/IIIa, integrin α11bβ3) and inhibit platelet aggregation in vitro. The peptides RGDS and RGDY(Me)‐NH2 were rapidly degraded when incubated in human, rat, and dog plasma. HPLC analysis indicated that amino acids were sequentially removed from the peptide N‐terminus, and this degradation was prevented by the aminopeptidase inhibitor bestatin. Analogs of RGDY(Me)‐NH2 with an acetylated or deleted α‐amino group were prepared. Both analogs were stable when incubated in plasma, blocked 125I‐fibrinogen binding to activated platelets (IC50= 10–30μm) and inhibited ADP induced platelet aggregation (IC50= 10–30μm). This study concludes that aminopeptidase rapidly degrades RGD peptides in plasma, an important issue for in vivo testing of RGD peptides and analogs. RGD analogs intrinsically stabilized against aminopeptidase are stable in plasma and are important tools for antithrombotic studies involving antagonism of gp IIb/IIIa.</description><subject>aggregation</subject><subject>Amino Acid Sequence</subject><subject>aminopeptidase</subject><subject>aminopeptidase: antagonist</subject><subject>Aminopeptidases - pharmacology</subject><subject>Binding Sites - drug effects</subject><subject>Biological and medical sciences</subject><subject>Blood. Blood coagulation. Reticuloendothelial system</subject><subject>Dose-Response Relationship, Drug</subject><subject>fibrinogen</subject><subject>Fibrinogen - antagonists & inhibitors</subject><subject>gp IIb/IIIa</subject><subject>integrin α11bβ3 platelet</subject><subject>Integrins - antagonists & inhibitors</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Pharmacology. Drug treatments</subject><subject>Platelet Aggregation - drug effects</subject><subject>Platelet Aggregation Inhibitors - metabolism</subject><subject>Platelet Aggregation Inhibitors - pharmacology</subject><subject>Platelet Membrane Glycoproteins - antagonists & inhibitors</subject><subject>platelets</subject><subject>Receptors, Immunologic</subject><subject>Receptors, Peptide</subject><subject>RGD analogs</subject><issn>0367-8377</issn><issn>1399-3011</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1991</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkUGP0zAQhS0EWsrCT0CKEOKW4Ind2OGCul22i1gtEgLBzZo4TnBxk2Cnov336yhVOSJ8sez3zbNnHiGvgGYQ19ttBqwsU0YBMihLyMaKAocyOzwii7P0mCwoK0QqmRBPybMQtpQyzkR-QS5ASMalXJBqtbNdP5hhtDUGk3gTbBixG5OVb9ONO6arMCTYoevbkKA3SVQrZxLbJYPDsMMo1vH001Z2nK5G48yYYNt60-Jo--45edKgC-bFab8k324-fF3fpnefNx_Xq7tU80LyVFeNlHpJq8bUtBA5agDUXGiZI0WEpaAF1bXU3MSekZuG85o1GgF0KUvNLsmb2Xfw_e-9CaPa2aCNc9iZfh-UyAsmuIR_glBAzoGKCL6bQe37ELxp1ODtDv1RAVVTEmqrpnGradxqSkKdklCHWPzy9Mq-2pn6b-k8-qi_PukYNLrGY6dtOGO8LKiQecTez9gf68zxPz6g1lfX17GR6JDODjFYczg7oP-lCsHEUn2_3yj55RPjP67u1S17ALMFte0</recordid><startdate>199108</startdate><enddate>199108</enddate><creator>FOK, K.AM F.</creator><creator>PANZER-KNODLE, SUSAN G.</creator><creator>NICHOLSON, NANCY S.</creator><creator>TJOENG, FOE S.</creator><creator>FEIGEN, LARRY P.</creator><creator>ADAMS, STEVEN P.</creator><general>Blackwell Publishing Ltd</general><general>Munksgaard</general><scope>BSCLL</scope><scope>IQODW</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>7QL</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>M81</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>199108</creationdate><title>Aminopeptidase resistant Arg-Gly-Asp analogs are stable in plasma and inhibit platelet aggregation</title><author>FOK, K.AM F. ; PANZER-KNODLE, SUSAN G. ; NICHOLSON, NANCY S. ; TJOENG, FOE S. ; FEIGEN, LARRY P. ; ADAMS, STEVEN P.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4684-cbf88c50bfed0672ac11ac47c82a0aa157060cd8c4e199a4ef44d3fca11c989c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1991</creationdate><topic>aggregation</topic><topic>Amino Acid Sequence</topic><topic>aminopeptidase</topic><topic>aminopeptidase: antagonist</topic><topic>Aminopeptidases - pharmacology</topic><topic>Binding Sites - drug effects</topic><topic>Biological and medical sciences</topic><topic>Blood. Blood coagulation. Reticuloendothelial system</topic><topic>Dose-Response Relationship, Drug</topic><topic>fibrinogen</topic><topic>Fibrinogen - antagonists & inhibitors</topic><topic>gp IIb/IIIa</topic><topic>integrin α11bβ3 platelet</topic><topic>Integrins - antagonists & inhibitors</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Pharmacology. Drug treatments</topic><topic>Platelet Aggregation - drug effects</topic><topic>Platelet Aggregation Inhibitors - metabolism</topic><topic>Platelet Aggregation Inhibitors - pharmacology</topic><topic>Platelet Membrane Glycoproteins - antagonists & inhibitors</topic><topic>platelets</topic><topic>Receptors, Immunologic</topic><topic>Receptors, Peptide</topic><topic>RGD analogs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>FOK, K.AM F.</creatorcontrib><creatorcontrib>PANZER-KNODLE, SUSAN G.</creatorcontrib><creatorcontrib>NICHOLSON, NANCY S.</creatorcontrib><creatorcontrib>TJOENG, FOE S.</creatorcontrib><creatorcontrib>FEIGEN, LARRY P.</creatorcontrib><creatorcontrib>ADAMS, STEVEN P.</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biochemistry Abstracts 3</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>International Journal of Peptide and Protein Research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>FOK, K.AM F.</au><au>PANZER-KNODLE, SUSAN G.</au><au>NICHOLSON, NANCY S.</au><au>TJOENG, FOE S.</au><au>FEIGEN, LARRY P.</au><au>ADAMS, STEVEN P.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aminopeptidase resistant Arg-Gly-Asp analogs are stable in plasma and inhibit platelet aggregation</atitle><jtitle>International Journal of Peptide and Protein Research</jtitle><addtitle>Int J Pept Protein Res</addtitle><date>1991-08</date><risdate>1991</risdate><volume>38</volume><issue>2</issue><spage>124</spage><epage>130</epage><pages>124-130</pages><issn>0367-8377</issn><eissn>1399-3011</eissn><coden>IJPPC3</coden><abstract>Tetrapeptides containing the sequence Arg‐Gly‐Asp (RGD) antagonize fibrinogen binding to its platelet receptor (gp IIb/IIIa, integrin α11bβ3) and inhibit platelet aggregation in vitro. The peptides RGDS and RGDY(Me)‐NH2 were rapidly degraded when incubated in human, rat, and dog plasma. HPLC analysis indicated that amino acids were sequentially removed from the peptide N‐terminus, and this degradation was prevented by the aminopeptidase inhibitor bestatin. Analogs of RGDY(Me)‐NH2 with an acetylated or deleted α‐amino group were prepared. Both analogs were stable when incubated in plasma, blocked 125I‐fibrinogen binding to activated platelets (IC50= 10–30μm) and inhibited ADP induced platelet aggregation (IC50= 10–30μm). This study concludes that aminopeptidase rapidly degrades RGD peptides in plasma, an important issue for in vivo testing of RGD peptides and analogs. RGD analogs intrinsically stabilized against aminopeptidase are stable in plasma and are important tools for antithrombotic studies involving antagonism of gp IIb/IIIa.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>1783488</pmid><doi>10.1111/j.1399-3011.1991.tb01419.x</doi><tpages>7</tpages></addata></record> |
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| identifier | ISSN: 0367-8377 |
| ispartof | International Journal of Peptide and Protein Research, 1991-08, Vol.38 (2), p.124-130 |
| issn | 0367-8377 1399-3011 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_72637481 |
| source | MEDLINE; Wiley Online Library All Journals |
| subjects | aggregation Amino Acid Sequence aminopeptidase aminopeptidase: antagonist Aminopeptidases - pharmacology Binding Sites - drug effects Biological and medical sciences Blood. Blood coagulation. Reticuloendothelial system Dose-Response Relationship, Drug fibrinogen Fibrinogen - antagonists & inhibitors gp IIb/IIIa integrin α11bβ3 platelet Integrins - antagonists & inhibitors Medical sciences Molecular Sequence Data Pharmacology. Drug treatments Platelet Aggregation - drug effects Platelet Aggregation Inhibitors - metabolism Platelet Aggregation Inhibitors - pharmacology Platelet Membrane Glycoproteins - antagonists & inhibitors platelets Receptors, Immunologic Receptors, Peptide RGD analogs |
| title | Aminopeptidase resistant Arg-Gly-Asp analogs are stable in plasma and inhibit platelet aggregation |
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