SAR by MS: Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus: Internal Ribosome Entry Site IIA Subdomain
A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' 1 with a K D ∼100 μM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further...
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| Veröffentlicht in: | Journal of medicinal chemistry 2005-11, Vol.48 (23), p.7099-7102 |
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| container_end_page | 7102 |
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| container_issue | 23 |
| container_start_page | 7099 |
| container_title | Journal of medicinal chemistry |
| container_volume | 48 |
| creator | Seth, Punit P Miyaji, Alycia Jefferson, Elizabeth A Sannes-Lowery, Kristin A Osgood, Stephen A Propp, Stephanie S Ranken, Ray Massire, Christian Sampath, Rangarajan Ecker, David J Swayze, Eric E Griffey, Richard H |
| description | A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' 1 with a K D ∼100 μM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure−activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their K D for the RNA target. |
| doi_str_mv | 10.1021/jm050815o |
| format | Article |
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The benzimidazole ‘hit' 1 with a K D ∼100 μM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure−activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their K D for the RNA target.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm050815o</identifier><identifier>PMID: 16279767</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Base Sequence ; Benzimidazoles - chemistry ; Benzimidazoles - pharmacology ; Benzimidazoles - toxicity ; Binding Sites ; Biological and medical sciences ; Cell Line ; Databases, Factual ; Hepacivirus - genetics ; Hepacivirus - physiology ; Hepatitis C virus ; Humans ; Mass Spectrometry ; Medical sciences ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Pharmacology. Drug treatments ; Quantitative Structure-Activity Relationship ; Ribosomes - chemistry ; Ribosomes - drug effects ; Ribosomes - metabolism ; RNA, Viral - chemistry ; RNA, Viral - metabolism ; Virus Replication</subject><ispartof>Journal of medicinal chemistry, 2005-11, Vol.48 (23), p.7099-7102</ispartof><rights>Copyright © 2005 American Chemical Society</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a478t-9a0006daba8760cd0a98d1322ea972596a079cd4e9f75fe31db76e4f150726e73</citedby><cites>FETCH-LOGICAL-a478t-9a0006daba8760cd0a98d1322ea972596a079cd4e9f75fe31db76e4f150726e73</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/jm050815o$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm050815o$$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=17278237$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16279767$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Seth, Punit P</creatorcontrib><creatorcontrib>Miyaji, Alycia</creatorcontrib><creatorcontrib>Jefferson, Elizabeth A</creatorcontrib><creatorcontrib>Sannes-Lowery, Kristin A</creatorcontrib><creatorcontrib>Osgood, Stephen A</creatorcontrib><creatorcontrib>Propp, Stephanie S</creatorcontrib><creatorcontrib>Ranken, Ray</creatorcontrib><creatorcontrib>Massire, Christian</creatorcontrib><creatorcontrib>Sampath, Rangarajan</creatorcontrib><creatorcontrib>Ecker, David J</creatorcontrib><creatorcontrib>Swayze, Eric E</creatorcontrib><creatorcontrib>Griffey, Richard H</creatorcontrib><title>SAR by MS: Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus: Internal Ribosome Entry Site IIA Subdomain</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' 1 with a K D ∼100 μM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure−activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their K D for the RNA target.</description><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Base Sequence</subject><subject>Benzimidazoles - chemistry</subject><subject>Benzimidazoles - pharmacology</subject><subject>Benzimidazoles - toxicity</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Databases, Factual</subject><subject>Hepacivirus - genetics</subject><subject>Hepacivirus - physiology</subject><subject>Hepatitis C virus</subject><subject>Humans</subject><subject>Mass Spectrometry</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Nucleic Acid Conformation</subject><subject>Pharmacology. Drug treatments</subject><subject>Quantitative Structure-Activity Relationship</subject><subject>Ribosomes - chemistry</subject><subject>Ribosomes - drug effects</subject><subject>Ribosomes - metabolism</subject><subject>RNA, Viral - chemistry</subject><subject>RNA, Viral - metabolism</subject><subject>Virus Replication</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1v0zAYgC0EYt3gwB9AvoDEIWA7H064dWFslbaCmlGO1pvkDbg4cbGTsd64ctmP3C8hpdV64WS98qPHfh9CXnD2ljPB361aFrOUx_YRmfBYsCBKWfSYTBgTIhCJCI_IsfcrxljIRfiUHPFEyEwmckLuiumClht6Vby___2HftC-sjfoNtQ2FOgcf9HcgPfbcTGfBqe6q3X3jRYtGEOvrMFqMOhpYx3tvyO9wDX0utee5nSp3eD_WWddj64DQxe6tN62SM-6fnyj0D3S2WxKi6GsbQu6e0aeNGA8Pt-fJ-TLx7Pr_CK4_HQ-y6eXAUQy7YMMxl2SGkpIZcKqmkGW1jwUAiGTIs4SYDKr6gizRsYNhrwuZYJRw2MmRYIyPCGvd961sz8H9L1qx83RGOjQDl7xLMzCMe0IvtmBlbPeO2zU2ukW3EZxprbx1UP8kX25lw5li_WB3NcegVd7AHwFpnHQVdofOClkKsItF-w47Xu8fbgH90ONFhmr68-FWqbzqMiXX1V-8ELl1coO29b-Px_8CwJXp4k</recordid><startdate>20051117</startdate><enddate>20051117</enddate><creator>Seth, Punit P</creator><creator>Miyaji, Alycia</creator><creator>Jefferson, Elizabeth A</creator><creator>Sannes-Lowery, Kristin A</creator><creator>Osgood, Stephen A</creator><creator>Propp, Stephanie S</creator><creator>Ranken, Ray</creator><creator>Massire, Christian</creator><creator>Sampath, Rangarajan</creator><creator>Ecker, David J</creator><creator>Swayze, Eric E</creator><creator>Griffey, Richard H</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><scope>7U9</scope><scope>H94</scope></search><sort><creationdate>20051117</creationdate><title>SAR by MS: Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus: Internal Ribosome Entry Site IIA Subdomain</title><author>Seth, Punit P ; Miyaji, Alycia ; Jefferson, Elizabeth A ; Sannes-Lowery, Kristin A ; Osgood, Stephen A ; Propp, Stephanie S ; Ranken, Ray ; Massire, Christian ; Sampath, Rangarajan ; Ecker, David J ; Swayze, Eric E ; Griffey, Richard H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a478t-9a0006daba8760cd0a98d1322ea972596a079cd4e9f75fe31db76e4f150726e73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Base Sequence</topic><topic>Benzimidazoles - chemistry</topic><topic>Benzimidazoles - pharmacology</topic><topic>Benzimidazoles - toxicity</topic><topic>Binding Sites</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Databases, Factual</topic><topic>Hepacivirus - genetics</topic><topic>Hepacivirus - physiology</topic><topic>Hepatitis C virus</topic><topic>Humans</topic><topic>Mass Spectrometry</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Nucleic Acid Conformation</topic><topic>Pharmacology. 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Med. Chem</addtitle><date>2005-11-17</date><risdate>2005</risdate><volume>48</volume><issue>23</issue><spage>7099</spage><epage>7102</epage><pages>7099-7102</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A new class of small molecules that bind the HCV RNA IRES IIA subdomain with sub-micromolar affinity is reported. The benzimidazole ‘hit' 1 with a K D ∼100 μM to a 29-mer RNA model of Domain IIA was identified from a 180000-member library using mass spectrometry-based screening methods. Further MS-assisted SAR (structure−activity relationships) studies afforded benzimidazole derivatives with sub-micromolar binding affinity for the IIA RNA construct. The optimized benzimidazoles demonstrated activity in a cellular replicon assay at concentrations comparable to their K D for the RNA target.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16279767</pmid><doi>10.1021/jm050815o</doi><tpages>4</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 2005-11, Vol.48 (23), p.7099-7102 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Base Sequence Benzimidazoles - chemistry Benzimidazoles - pharmacology Benzimidazoles - toxicity Binding Sites Biological and medical sciences Cell Line Databases, Factual Hepacivirus - genetics Hepacivirus - physiology Hepatitis C virus Humans Mass Spectrometry Medical sciences Models, Molecular Molecular Sequence Data Nucleic Acid Conformation Pharmacology. Drug treatments Quantitative Structure-Activity Relationship Ribosomes - chemistry Ribosomes - drug effects Ribosomes - metabolism RNA, Viral - chemistry RNA, Viral - metabolism Virus Replication |
| title | SAR by MS: Discovery of a New Class of RNA-Binding Small Molecules for the Hepatitis C Virus: Internal Ribosome Entry Site IIA Subdomain |
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