Application of encoded library technology (ELT) to a protein–protein interaction target: Discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists
Encoded library technology (ELT) was utilized to identify a class of compounds that disrupt the interaction between lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) at submicromolar potency in both ELISA and cell adhesion assays. The inhibiti...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry 2014-04, Vol.22 (7), p.2353-2365 |
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| container_title | Bioorganic & medicinal chemistry |
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| creator | Kollmann, Christopher S. Bai, Xiaopeng Tsai, Ching-Hsuan Yang, Hongfang Lind, Kenneth E. Skinner, Steven R. Zhu, Zhengrong Israel, David I. Cuozzo, John W. Morgan, Barry A. Yuki, Koichi Xie, Can Springer, Timothy A. Shimaoka, Motomu Evindar, Ghotas |
| description | Encoded library technology (ELT) was utilized to identify a class of compounds that disrupt the interaction between lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) at submicromolar potency in both ELISA and cell adhesion assays.
The inhibition of protein–protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein. |
| doi_str_mv | 10.1016/j.bmc.2014.01.050 |
| format | Article |
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The inhibition of protein–protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein.</description><identifier>ISSN: 0968-0896</identifier><identifier>EISSN: 1464-3391</identifier><identifier>DOI: 10.1016/j.bmc.2014.01.050</identifier><identifier>PMID: 24593905</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Affinity-based selections ; Cell Adhesion - drug effects ; DNA-encoded libraries ; Dose-Response Relationship, Drug ; Drug Discovery ; Encoded Library Technology ; Humans ; Intercellular Adhesion Molecule 1 ; Jurkat Cells ; Ligands ; Lymphocyte Function-associated Antigen 1 ; Lymphocyte Function-Associated Antigen-1 - metabolism ; Molecular Structure ; Protein Binding - drug effects ; Protein-Protein Interactions ; Small Molecule Libraries - chemical synthesis ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry, 2014-04, Vol.22 (7), p.2353-2365</ispartof><rights>2014 Elsevier Ltd</rights><rights>Copyright © 2014 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c452t-1471a71672b5ec677b720bc70939c676c2466dac13e2cb2718d08e6059786cd83</citedby><cites>FETCH-LOGICAL-c452t-1471a71672b5ec677b720bc70939c676c2466dac13e2cb2718d08e6059786cd83</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmc.2014.01.050$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3548,27923,27924,45994</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24593905$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kollmann, Christopher S.</creatorcontrib><creatorcontrib>Bai, Xiaopeng</creatorcontrib><creatorcontrib>Tsai, Ching-Hsuan</creatorcontrib><creatorcontrib>Yang, Hongfang</creatorcontrib><creatorcontrib>Lind, Kenneth E.</creatorcontrib><creatorcontrib>Skinner, Steven R.</creatorcontrib><creatorcontrib>Zhu, Zhengrong</creatorcontrib><creatorcontrib>Israel, David I.</creatorcontrib><creatorcontrib>Cuozzo, John W.</creatorcontrib><creatorcontrib>Morgan, Barry A.</creatorcontrib><creatorcontrib>Yuki, Koichi</creatorcontrib><creatorcontrib>Xie, Can</creatorcontrib><creatorcontrib>Springer, Timothy A.</creatorcontrib><creatorcontrib>Shimaoka, Motomu</creatorcontrib><creatorcontrib>Evindar, Ghotas</creatorcontrib><title>Application of encoded library technology (ELT) to a protein–protein interaction target: Discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists</title><title>Bioorganic & medicinal chemistry</title><addtitle>Bioorg Med Chem</addtitle><description>Encoded library technology (ELT) was utilized to identify a class of compounds that disrupt the interaction between lymphocyte function-associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) at submicromolar potency in both ELISA and cell adhesion assays.
The inhibition of protein–protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein.</description><subject>Affinity-based selections</subject><subject>Cell Adhesion - drug effects</subject><subject>DNA-encoded libraries</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Encoded Library Technology</subject><subject>Humans</subject><subject>Intercellular Adhesion Molecule 1</subject><subject>Jurkat Cells</subject><subject>Ligands</subject><subject>Lymphocyte Function-associated Antigen 1</subject><subject>Lymphocyte Function-Associated Antigen-1 - metabolism</subject><subject>Molecular Structure</subject><subject>Protein Binding - drug effects</subject><subject>Protein-Protein Interactions</subject><subject>Small Molecule Libraries - chemical synthesis</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0968-0896</issn><issn>1464-3391</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcGO0zAURSMEYsrAB7BBXnYWCe85iZPAqhpmAKkSm2FtOc5rxlVqF9sdqTv-gQ_iX_gSnGlhiVjZfrr3yO_eLHuNUCCgeLst-p0uOGBVABZQw5NsgZWo8rLs8Gm2gE60ObSduMhehLAFAF51-Dy74FXdlR3Ui-znar-fjFbROMvchpHVbqCBTab3yh9ZJH1v3eTGI1verO-uWHRMsb13kYz99f3H-caMjeSVfsRE5UeK79gHE7R7oERJ4GRKShuZnlQI82S2jD55p-Nuf-_0MRLbHOwjI08ap42K6SvKRjOSZciW69tVjlfzRI3OmhDDy-zZRk2BXp3Py-zr7c3d9ad8_eXj5-vVOtdVzWOOVYOqQdHwviYtmqZvOPS6gRRDegrNKyEGpbEkrnveYDtASwLqrmmFHtryMlueuGnhbwcKUe7SdjRNypI7BIk1h7KtoWv-Q4rYcl6VkKR4kmrvQvC0kXtvdil3iSDniuVWporlXLEElKni5Hlzxh_6HQ1_HX86TYL3JwGlPB4MeRm0Sb3SYDzpKAdn_oH_DYmruZI</recordid><startdate>20140401</startdate><enddate>20140401</enddate><creator>Kollmann, Christopher S.</creator><creator>Bai, Xiaopeng</creator><creator>Tsai, Ching-Hsuan</creator><creator>Yang, Hongfang</creator><creator>Lind, Kenneth E.</creator><creator>Skinner, Steven R.</creator><creator>Zhu, Zhengrong</creator><creator>Israel, David I.</creator><creator>Cuozzo, John W.</creator><creator>Morgan, Barry A.</creator><creator>Yuki, Koichi</creator><creator>Xie, Can</creator><creator>Springer, Timothy A.</creator><creator>Shimaoka, Motomu</creator><creator>Evindar, Ghotas</creator><general>Elsevier Ltd</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><scope>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope></search><sort><creationdate>20140401</creationdate><title>Application of encoded library technology (ELT) to a protein–protein interaction target: Discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists</title><author>Kollmann, Christopher S. ; 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The inhibition of protein–protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>24593905</pmid><doi>10.1016/j.bmc.2014.01.050</doi><tpages>13</tpages></addata></record> |
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| identifier | ISSN: 0968-0896 |
| ispartof | Bioorganic & medicinal chemistry, 2014-04, Vol.22 (7), p.2353-2365 |
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| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Affinity-based selections Cell Adhesion - drug effects DNA-encoded libraries Dose-Response Relationship, Drug Drug Discovery Encoded Library Technology Humans Intercellular Adhesion Molecule 1 Jurkat Cells Ligands Lymphocyte Function-associated Antigen 1 Lymphocyte Function-Associated Antigen-1 - metabolism Molecular Structure Protein Binding - drug effects Protein-Protein Interactions Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Structure-Activity Relationship |
| title | Application of encoded library technology (ELT) to a protein–protein interaction target: Discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists |
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