Aminoacyl-tRNA Synthetase Inhibitors as Potent and Synergistic Immunosuppressants
The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5′-O-(N-l-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found these compounds to have potent immunosuppressi...
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-05, Vol.51 (10), p.3020-3029 |
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| container_end_page | 3029 |
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| container_issue | 10 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 51 |
| creator | Van de Vijver, Pieter Ostrowski, Tomasz Sproat, Brian Goebels, Jozef Rutgeerts, Omer Van Aerschot, Arthur Waer, Mark Herdewijn, Piet |
| description | The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5′-O-(N-l-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found these compounds to have potent immunosuppressive activity. Also, we found that combinations of these compounds inhibited the immune response synergistically. Based on these data, analogues with modifications at the aminoacyl and ribose moieties were designed and evaluated, and several of these showed high immunosuppressive potency, with one compound having an IC50 of 80 nM, when tested in a cellular mixed lymphocyte reaction assay. Apart from showing the potential of aminoacyl-tRNA synthetase inhibitors as immunosuppressants, the current study also provides arguments for careful evaluation of the immunosuppressive activity of developmental antibacterials that target these enzymes. |
| doi_str_mv | 10.1021/jm8000746 |
| format | Article |
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In screening analogues of 5′-O-(N-l-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found these compounds to have potent immunosuppressive activity. Also, we found that combinations of these compounds inhibited the immune response synergistically. Based on these data, analogues with modifications at the aminoacyl and ribose moieties were designed and evaluated, and several of these showed high immunosuppressive potency, with one compound having an IC50 of 80 nM, when tested in a cellular mixed lymphocyte reaction assay. Apart from showing the potential of aminoacyl-tRNA synthetase inhibitors as immunosuppressants, the current study also provides arguments for careful evaluation of the immunosuppressive activity of developmental antibacterials that target these enzymes.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm8000746</identifier><identifier>PMID: 18438987</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Adenosine - analogs & derivatives ; Adenosine - chemical synthesis ; Adenosine - pharmacology ; Amino Acids - chemical synthesis ; Amino Acids - pharmacology ; Amino Acyl-tRNA Synthetases - antagonists & inhibitors ; Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Biological and medical sciences ; Cells, Cultured ; Drug Synergism ; Humans ; Immunomodulators ; Immunosuppressive Agents - chemical synthesis ; Immunosuppressive Agents - chemistry ; Immunosuppressive Agents - pharmacology ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - immunology ; Lymphocyte Culture Test, Mixed ; Medical sciences ; Pharmacology. Drug treatments ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2008-05, Vol.51 (10), p.3020-3029</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a447t-93fe08ddf6bcbb88642733055f612e816239fa953394c3e5f95b027256b11b13</citedby><cites>FETCH-LOGICAL-a447t-93fe08ddf6bcbb88642733055f612e816239fa953394c3e5f95b027256b11b13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm8000746$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm8000746$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20349461$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18438987$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Van de Vijver, Pieter</creatorcontrib><creatorcontrib>Ostrowski, Tomasz</creatorcontrib><creatorcontrib>Sproat, Brian</creatorcontrib><creatorcontrib>Goebels, Jozef</creatorcontrib><creatorcontrib>Rutgeerts, Omer</creatorcontrib><creatorcontrib>Van Aerschot, Arthur</creatorcontrib><creatorcontrib>Waer, Mark</creatorcontrib><creatorcontrib>Herdewijn, Piet</creatorcontrib><title>Aminoacyl-tRNA Synthetase Inhibitors as Potent and Synergistic Immunosuppressants</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5′-O-(N-l-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found these compounds to have potent immunosuppressive activity. Also, we found that combinations of these compounds inhibited the immune response synergistically. Based on these data, analogues with modifications at the aminoacyl and ribose moieties were designed and evaluated, and several of these showed high immunosuppressive potency, with one compound having an IC50 of 80 nM, when tested in a cellular mixed lymphocyte reaction assay. Apart from showing the potential of aminoacyl-tRNA synthetase inhibitors as immunosuppressants, the current study also provides arguments for careful evaluation of the immunosuppressive activity of developmental antibacterials that target these enzymes.</description><subject>Adenosine - analogs & derivatives</subject><subject>Adenosine - chemical synthesis</subject><subject>Adenosine - pharmacology</subject><subject>Amino Acids - chemical synthesis</subject><subject>Amino Acids - pharmacology</subject><subject>Amino Acyl-tRNA Synthetases - antagonists & inhibitors</subject><subject>Antibacterial agents</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Drug Synergism</subject><subject>Humans</subject><subject>Immunomodulators</subject><subject>Immunosuppressive Agents - chemical synthesis</subject><subject>Immunosuppressive Agents - chemistry</subject><subject>Immunosuppressive Agents - pharmacology</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - immunology</subject><subject>Lymphocyte Culture Test, Mixed</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0LtOwzAUBmALgWi5DLwAysLAEPAtjjNWFZeKUloaidGyU5umNE5kOxJ9e1K1ahemM5xP5_IDcIPgA4IYPa4qDiFMKTsBfZRgGFMO6SnoQ4hxjBkmPXDh_aozBGFyDnqIU8IznvbBbFCVtpbFZh2Hz8kgmm9sWOogvY5GdlmqMtTOR9JH0zpoGyJpF1uj3XfpQ1lEo6pqbe3bpnHae2mDvwJnRq69vt7XS5A_P-XD13j88TIaDsaxpDQNcUaMhnyxMEwVSnHOKE4JgUliGMKao-7qzMgsISSjBdGJyRIFcYoTphBSiFyC-93YwtXeO21E48pKuo1AUGxTEYdUOnu7s02rKr04yn0MHbjbA-kLuTZO2qL0B4choRll26XxznXP699DX7ofwVKSJiKfzsXbMOd0MvsS78e5svBiVbfOdon8c-AfhlaEfg</recordid><startdate>20080522</startdate><enddate>20080522</enddate><creator>Van de Vijver, Pieter</creator><creator>Ostrowski, Tomasz</creator><creator>Sproat, Brian</creator><creator>Goebels, Jozef</creator><creator>Rutgeerts, Omer</creator><creator>Van Aerschot, Arthur</creator><creator>Waer, Mark</creator><creator>Herdewijn, Piet</creator><general>American Chemical Society</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></search><sort><creationdate>20080522</creationdate><title>Aminoacyl-tRNA Synthetase Inhibitors as Potent and Synergistic Immunosuppressants</title><author>Van de Vijver, Pieter ; Ostrowski, Tomasz ; Sproat, Brian ; Goebels, Jozef ; Rutgeerts, Omer ; Van Aerschot, Arthur ; Waer, Mark ; Herdewijn, Piet</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a447t-93fe08ddf6bcbb88642733055f612e816239fa953394c3e5f95b027256b11b13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adenosine - analogs & derivatives</topic><topic>Adenosine - chemical synthesis</topic><topic>Adenosine - pharmacology</topic><topic>Amino Acids - chemical synthesis</topic><topic>Amino Acids - pharmacology</topic><topic>Amino Acyl-tRNA Synthetases - antagonists & inhibitors</topic><topic>Antibacterial agents</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Drug Synergism</topic><topic>Humans</topic><topic>Immunomodulators</topic><topic>Immunosuppressive Agents - chemical synthesis</topic><topic>Immunosuppressive Agents - chemistry</topic><topic>Immunosuppressive Agents - pharmacology</topic><topic>Leukocytes, Mononuclear - drug effects</topic><topic>Leukocytes, Mononuclear - immunology</topic><topic>Lymphocyte Culture Test, Mixed</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Van de Vijver, Pieter</creatorcontrib><creatorcontrib>Ostrowski, Tomasz</creatorcontrib><creatorcontrib>Sproat, Brian</creatorcontrib><creatorcontrib>Goebels, Jozef</creatorcontrib><creatorcontrib>Rutgeerts, Omer</creatorcontrib><creatorcontrib>Van Aerschot, Arthur</creatorcontrib><creatorcontrib>Waer, Mark</creatorcontrib><creatorcontrib>Herdewijn, Piet</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><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Van de Vijver, Pieter</au><au>Ostrowski, Tomasz</au><au>Sproat, Brian</au><au>Goebels, Jozef</au><au>Rutgeerts, Omer</au><au>Van Aerschot, Arthur</au><au>Waer, Mark</au><au>Herdewijn, Piet</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aminoacyl-tRNA Synthetase Inhibitors as Potent and Synergistic Immunosuppressants</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-05-22</date><risdate>2008</risdate><volume>51</volume><issue>10</issue><spage>3020</spage><epage>3029</epage><pages>3020-3029</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The aminoacyl-tRNA synthetase family of enzymes is the target of many antibacterials and inhibitors of eukaryotic hyperproliferation. In screening analogues of 5′-O-(N-l-aminoacyl)-sulfamoyladenosine containing all 20 proteinogenic amino acids, we found these compounds to have potent immunosuppressive activity. Also, we found that combinations of these compounds inhibited the immune response synergistically. Based on these data, analogues with modifications at the aminoacyl and ribose moieties were designed and evaluated, and several of these showed high immunosuppressive potency, with one compound having an IC50 of 80 nM, when tested in a cellular mixed lymphocyte reaction assay. Apart from showing the potential of aminoacyl-tRNA synthetase inhibitors as immunosuppressants, the current study also provides arguments for careful evaluation of the immunosuppressive activity of developmental antibacterials that target these enzymes.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>18438987</pmid><doi>10.1021/jm8000746</doi><tpages>10</tpages></addata></record> |
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| subjects | Adenosine - analogs & derivatives Adenosine - chemical synthesis Adenosine - pharmacology Amino Acids - chemical synthesis Amino Acids - pharmacology Amino Acyl-tRNA Synthetases - antagonists & inhibitors Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Biological and medical sciences Cells, Cultured Drug Synergism Humans Immunomodulators Immunosuppressive Agents - chemical synthesis Immunosuppressive Agents - chemistry Immunosuppressive Agents - pharmacology Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - immunology Lymphocyte Culture Test, Mixed Medical sciences Pharmacology. Drug treatments Structure-Activity Relationship |
| title | Aminoacyl-tRNA Synthetase Inhibitors as Potent and Synergistic Immunosuppressants |
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