Characterization of a Respiratory Syncytial Virus L Protein Inhibitor
The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a...
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| Veröffentlicht in: | Antimicrobial agents and chemotherapy 2014-07, Vol.58 (7), p.3867-3873 |
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| container_title | Antimicrobial agents and chemotherapy |
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| creator | TIONG-YIP, Choi-Lai ASCHENBRENNER, Lisa JOHNSON, Kenneth D MCLAUGHLIN, Robert E JUN FAN CHALLA, SreeRupa HUI XIONG QIN YU |
| description | The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibitor with strong antiviral activity against both RSV A and B subtypes and no detectable cytotoxicity. This compound, AZ-27, was equally active against RSV live viruses and subgenomic replicons and demonstrated advantages over other classes of RSV inhibitors in time-of-addition and cell line dependency studies. Resistance studies identified a dominant mutation in the putative capping enzyme domain of L protein, which conferred strong resistance to the AZ-27 series but not other classes of RSV inhibitors, supporting RSV L protein as the direct target for AZ-27. This novel and broad-spectrum RSV L polymerase inhibitor may pave the way toward an efficacious RSV therapeutic and provide a new tool for interrogation of the L protein function. |
| doi_str_mv | 10.1128/AAC.02540-14 |
| format | Article |
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The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibitor with strong antiviral activity against both RSV A and B subtypes and no detectable cytotoxicity. This compound, AZ-27, was equally active against RSV live viruses and subgenomic replicons and demonstrated advantages over other classes of RSV inhibitors in time-of-addition and cell line dependency studies. Resistance studies identified a dominant mutation in the putative capping enzyme domain of L protein, which conferred strong resistance to the AZ-27 series but not other classes of RSV inhibitors, supporting RSV L protein as the direct target for AZ-27. This novel and broad-spectrum RSV L polymerase inhibitor may pave the way toward an efficacious RSV therapeutic and provide a new tool for interrogation of the L protein function.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/AAC.02540-14</identifier><identifier>PMID: 24777090</identifier><identifier>CODEN: AACHAX</identifier><language>eng</language><publisher>Washington, DC: American Society for Microbiology</publisher><subject>Amino Acid Sequence ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral Agents ; Antiviral Agents - pharmacology ; Benzazepines ; Benzazepines - pharmacology ; Biological and medical sciences ; Cell Line ; Cell Survival - drug effects ; Cyclopropanes ; Cyclopropanes - pharmacology ; Drug Resistance, Viral ; Human viral diseases ; Humans ; Infectious diseases ; Medical sciences ; Molecular Sequence Data ; Niacinamide ; Niacinamide - analogs & derivatives ; Niacinamide - pharmacology ; Pharmacology. Drug treatments ; Polymerase Chain Reaction ; Replicon - genetics ; Respiratory syncytial virus ; Respiratory Syncytial Virus Infections ; Respiratory Syncytial Virus Infections - virology ; Respiratory Syncytial Virus, Human ; Respiratory Syncytial Virus, Human - drug effects ; RNA Replicase ; RNA Replicase - antagonists & inhibitors ; Viral diseases ; Viral diseases of the respiratory system and ent viral diseases ; Viral Proteins ; Viral Proteins - antagonists & inhibitors</subject><ispartof>Antimicrobial agents and chemotherapy, 2014-07, Vol.58 (7), p.3867-3873</ispartof><rights>2015 INIST-CNRS</rights><rights>Copyright © 2014, American Society for Microbiology. All Rights Reserved.</rights><rights>Copyright © 2014, American Society for Microbiology. All Rights Reserved. 2014 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a481t-538f239541e613ceb106de5b82e6430ac15450db576852c4353ebea7774b066d3</citedby><cites>FETCH-LOGICAL-a481t-538f239541e613ceb106de5b82e6430ac15450db576852c4353ebea7774b066d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068518/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068518/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28577243$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24777090$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>TIONG-YIP, Choi-Lai</creatorcontrib><creatorcontrib>ASCHENBRENNER, Lisa</creatorcontrib><creatorcontrib>JOHNSON, Kenneth D</creatorcontrib><creatorcontrib>MCLAUGHLIN, Robert E</creatorcontrib><creatorcontrib>JUN FAN</creatorcontrib><creatorcontrib>CHALLA, SreeRupa</creatorcontrib><creatorcontrib>HUI XIONG</creatorcontrib><creatorcontrib>QIN YU</creatorcontrib><title>Characterization of a Respiratory Syncytial Virus L Protein Inhibitor</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. 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Antiparasitic agents</subject><subject>Antiviral Agents</subject><subject>Antiviral Agents - pharmacology</subject><subject>Benzazepines</subject><subject>Benzazepines - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cell Survival - drug effects</subject><subject>Cyclopropanes</subject><subject>Cyclopropanes - pharmacology</subject><subject>Drug Resistance, Viral</subject><subject>Human viral diseases</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Niacinamide</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Polymerase Chain Reaction</subject><subject>Replicon - genetics</subject><subject>Respiratory syncytial virus</subject><subject>Respiratory Syncytial Virus Infections</subject><subject>Respiratory Syncytial Virus Infections - virology</subject><subject>Respiratory Syncytial Virus, Human</subject><subject>Respiratory Syncytial Virus, Human - drug effects</subject><subject>RNA Replicase</subject><subject>RNA Replicase - antagonists & inhibitors</subject><subject>Viral diseases</subject><subject>Viral diseases of the respiratory system and ent viral diseases</subject><subject>Viral Proteins</subject><subject>Viral Proteins - antagonists & inhibitors</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtrGzEURkVpiB23u67LbAoJZFxp9BjNJmCGJA0YGtqkW3FH1sQKY8mRZgLOr48Su3ksCl1dxD0cvqsPoS8ETwkp5PfZrJ7igjOcE_YBjQmuZC54JT6iMcZC5ExiNkIHMd7i9OYV3kejgpVliSs8Rqf1EgLo3gT7AL31LvNtBtkvE9c2QO_DJvu9cXrTW-iyPzYMMZtnl8H3xrrswi1tYxP0Ce210EXzeTcn6Prs9Kr-kc9_nl_Us3kOTJI-51S2Ba04I0YQqk1DsFgY3sjCCEYxaMIZx4uGl0LyQjPKqWkMpKysSacs6ASdbL3roVmZhTauD9CpdbArCBvlwar3G2eX6sbfK4aTkcgkONwJgr8bTOzVykZtug6c8UNUKUAlKGEpzn-gpRScCZHQ4y2qg48xmPYlEcHqqSSVSlLPJSnyZD7a4hBXhbr1Q3Dp0_7Ffn178Yv4b4MJ-LYDIGro2gBO2_jKSV6WBaP0EWappWQ</recordid><startdate>20140701</startdate><enddate>20140701</enddate><creator>TIONG-YIP, Choi-Lai</creator><creator>ASCHENBRENNER, Lisa</creator><creator>JOHNSON, Kenneth D</creator><creator>MCLAUGHLIN, Robert E</creator><creator>JUN FAN</creator><creator>CHALLA, SreeRupa</creator><creator>HUI XIONG</creator><creator>QIN YU</creator><general>American Society for Microbiology</general><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>7T7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140701</creationdate><title>Characterization of a Respiratory Syncytial Virus L Protein Inhibitor</title><author>TIONG-YIP, Choi-Lai ; ASCHENBRENNER, Lisa ; JOHNSON, Kenneth D ; MCLAUGHLIN, Robert E ; JUN FAN ; CHALLA, SreeRupa ; HUI XIONG ; QIN YU</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a481t-538f239541e613ceb106de5b82e6430ac15450db576852c4353ebea7774b066d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Amino Acid Sequence</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral Agents</topic><topic>Antiviral Agents - pharmacology</topic><topic>Benzazepines</topic><topic>Benzazepines - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Cell Survival - drug effects</topic><topic>Cyclopropanes</topic><topic>Cyclopropanes - pharmacology</topic><topic>Drug Resistance, Viral</topic><topic>Human viral diseases</topic><topic>Humans</topic><topic>Infectious diseases</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Niacinamide</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Polymerase Chain Reaction</topic><topic>Replicon - genetics</topic><topic>Respiratory syncytial virus</topic><topic>Respiratory Syncytial Virus Infections</topic><topic>Respiratory Syncytial Virus Infections - virology</topic><topic>Respiratory Syncytial Virus, Human</topic><topic>Respiratory Syncytial Virus, Human - drug effects</topic><topic>RNA Replicase</topic><topic>RNA Replicase - antagonists & inhibitors</topic><topic>Viral diseases</topic><topic>Viral diseases of the respiratory system and ent viral diseases</topic><topic>Viral Proteins</topic><topic>Viral Proteins - antagonists & inhibitors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>TIONG-YIP, Choi-Lai</creatorcontrib><creatorcontrib>ASCHENBRENNER, Lisa</creatorcontrib><creatorcontrib>JOHNSON, Kenneth D</creatorcontrib><creatorcontrib>MCLAUGHLIN, Robert E</creatorcontrib><creatorcontrib>JUN FAN</creatorcontrib><creatorcontrib>CHALLA, SreeRupa</creatorcontrib><creatorcontrib>HUI XIONG</creatorcontrib><creatorcontrib>QIN YU</creatorcontrib><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>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>TIONG-YIP, Choi-Lai</au><au>ASCHENBRENNER, Lisa</au><au>JOHNSON, Kenneth D</au><au>MCLAUGHLIN, Robert E</au><au>JUN FAN</au><au>CHALLA, SreeRupa</au><au>HUI XIONG</au><au>QIN YU</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of a Respiratory Syncytial Virus L Protein Inhibitor</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2014-07-01</date><risdate>2014</risdate><volume>58</volume><issue>7</issue><spage>3867</spage><epage>3873</epage><pages>3867-3873</pages><issn>0066-4804</issn><eissn>1098-6596</eissn><coden>AACHAX</coden><abstract>The respiratory syncytial virus (RSV) L protein is a viral RNA-dependent RNA polymerase that contains multiple enzyme activities required for RSV replication. The RSV L inhibitors described in literature are limited by their cytotoxicity or the lack of RSV B subtype coverage. Here, we characterize a new RSV L inhibitor with strong antiviral activity against both RSV A and B subtypes and no detectable cytotoxicity. This compound, AZ-27, was equally active against RSV live viruses and subgenomic replicons and demonstrated advantages over other classes of RSV inhibitors in time-of-addition and cell line dependency studies. Resistance studies identified a dominant mutation in the putative capping enzyme domain of L protein, which conferred strong resistance to the AZ-27 series but not other classes of RSV inhibitors, supporting RSV L protein as the direct target for AZ-27. This novel and broad-spectrum RSV L polymerase inhibitor may pave the way toward an efficacious RSV therapeutic and provide a new tool for interrogation of the L protein function.</abstract><cop>Washington, DC</cop><pub>American Society for Microbiology</pub><pmid>24777090</pmid><doi>10.1128/AAC.02540-14</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Antimicrobial agents and chemotherapy, 2014-07, Vol.58 (7), p.3867-3873 |
| issn | 0066-4804 1098-6596 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Amino Acid Sequence Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral Agents Antiviral Agents - pharmacology Benzazepines Benzazepines - pharmacology Biological and medical sciences Cell Line Cell Survival - drug effects Cyclopropanes Cyclopropanes - pharmacology Drug Resistance, Viral Human viral diseases Humans Infectious diseases Medical sciences Molecular Sequence Data Niacinamide Niacinamide - analogs & derivatives Niacinamide - pharmacology Pharmacology. Drug treatments Polymerase Chain Reaction Replicon - genetics Respiratory syncytial virus Respiratory Syncytial Virus Infections Respiratory Syncytial Virus Infections - virology Respiratory Syncytial Virus, Human Respiratory Syncytial Virus, Human - drug effects RNA Replicase RNA Replicase - antagonists & inhibitors Viral diseases Viral diseases of the respiratory system and ent viral diseases Viral Proteins Viral Proteins - antagonists & inhibitors |
| title | Characterization of a Respiratory Syncytial Virus L Protein Inhibitor |
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