Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis
T-705 (favipiravir) is a new antiviral agent in advanced clinical development for influenza therapy. It is supposed to act as an alternative substrate for the viral polymerase, causing inhibition of viral RNA synthesis or virus mutagenesis. These mechanisms were also proposed for ribavirin, an estab...
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description | T-705 (favipiravir) is a new antiviral agent in advanced clinical development for influenza therapy. It is supposed to act as an alternative substrate for the viral polymerase, causing inhibition of viral RNA synthesis or virus mutagenesis. These mechanisms were also proposed for ribavirin, an established and broad antiviral drug that shares structural similarity with T-705. We here performed a comparative analysis of the effects of T-705 and ribavirin on influenza virus and host cell functions. Influenza virus-infected cell cultures were exposed to T-705 or ribavirin during single or serial virus passaging. The effects on viral RNA synthesis and infectious virus yield were determined and mutations appearing in the viral genome were detected by whole-genome virus sequencing. In addition, the cellular nucleotide pools as well as direct inhibition of the viral polymerase enzyme were quantified. We demonstrate that the anti-influenza virus effect of ribavirin is based on IMP dehydrogenase inhibition, which results in fast and profound GTP depletion and an imbalance in the nucleotide pools. In contrast, T-705 acts as a potent and GTP-competitive inhibitor of the viral polymerase. In infected cells, viral RNA synthesis is completely inhibited by T-705 or ribavirin at ≥50 μM, whereas exposure to lower drug concentrations induces formation of noninfectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is 2-fold higher for T-705 than for ribavirin. Hence, T-705 and ribavirin both act as purine pseudobases but profoundly differ with regard to the mechanism behind their antiviral and mutagenic effects on influenza virus. |
doi_str_mv | 10.1128/AAC.01156-16 |
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It is supposed to act as an alternative substrate for the viral polymerase, causing inhibition of viral RNA synthesis or virus mutagenesis. These mechanisms were also proposed for ribavirin, an established and broad antiviral drug that shares structural similarity with T-705. We here performed a comparative analysis of the effects of T-705 and ribavirin on influenza virus and host cell functions. Influenza virus-infected cell cultures were exposed to T-705 or ribavirin during single or serial virus passaging. The effects on viral RNA synthesis and infectious virus yield were determined and mutations appearing in the viral genome were detected by whole-genome virus sequencing. In addition, the cellular nucleotide pools as well as direct inhibition of the viral polymerase enzyme were quantified. We demonstrate that the anti-influenza virus effect of ribavirin is based on IMP dehydrogenase inhibition, which results in fast and profound GTP depletion and an imbalance in the nucleotide pools. In contrast, T-705 acts as a potent and GTP-competitive inhibitor of the viral polymerase. In infected cells, viral RNA synthesis is completely inhibited by T-705 or ribavirin at ≥50 μM, whereas exposure to lower drug concentrations induces formation of noninfectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is 2-fold higher for T-705 than for ribavirin. Hence, T-705 and ribavirin both act as purine pseudobases but profoundly differ with regard to the mechanism behind their antiviral and mutagenic effects on influenza virus.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/AAC.01156-16</identifier><identifier>PMID: 27572398</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject><![CDATA[A549 Cells ; Amides ; Amides - chemistry ; Amides - pharmacology ; Animals ; Antiviral Agents ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Chick Embryo ; DNA-Directed RNA Polymerases - antagonists & inhibitors ; DNA-Directed RNA Polymerases - genetics ; DNA-Directed RNA Polymerases - metabolism ; Dogs ; Gene Expression Regulation, Viral ; Humans ; IMP Dehydrogenase - antagonists & inhibitors ; IMP Dehydrogenase - genetics ; IMP Dehydrogenase - metabolism ; Influenza A Virus, H1N1 Subtype ; Influenza A Virus, H1N1 Subtype - drug effects ; Influenza A Virus, H1N1 Subtype - genetics ; Influenza A Virus, H1N1 Subtype - growth & development ; Influenza A Virus, H1N1 Subtype - metabolism ; Influenza A Virus, H3N2 Subtype ; Influenza A Virus, H3N2 Subtype - drug effects ; Influenza A Virus, H3N2 Subtype - genetics ; Influenza A Virus, H3N2 Subtype - growth & development ; Influenza A Virus, H3N2 Subtype - metabolism ; Madin Darby Canine Kidney Cells ; Mutation - drug effects ; Orthomyxoviridae ; Pyrazines ; Pyrazines - chemistry ; Pyrazines - pharmacology ; Reassortant Viruses ; Reassortant Viruses - drug effects ; Reassortant Viruses - genetics ; Reassortant Viruses - growth & development ; Reassortant Viruses - metabolism ; Ribavirin ; Ribavirin - chemistry ; Ribavirin - pharmacology ; RNA, Viral - antagonists & inhibitors ; RNA, Viral - biosynthesis ; Sequence Analysis, RNA ; Structure-Activity Relationship ; Viral Proteins - antagonists & inhibitors ; Viral Proteins - genetics ; Viral Proteins - metabolism ; Virus Replication - drug effects]]></subject><ispartof>Antimicrobial agents and chemotherapy, 2016-11, Vol.60 (11), p.6679-6691</ispartof><rights>Copyright © 2016, American Society for Microbiology. All Rights Reserved.</rights><rights>Copyright © 2016, American Society for Microbiology. All Rights Reserved. 2016 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a451t-57854ba8e0a57fac1e649394ce7a4150678a00c8608f194bd7ce4d85dc7bb1ba3</citedby><cites>FETCH-LOGICAL-a451t-57854ba8e0a57fac1e649394ce7a4150678a00c8608f194bd7ce4d85dc7bb1ba3</cites><orcidid>0000-0001-6547-5283</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075073/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075073/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27572398$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vanderlinden, Evelien</creatorcontrib><creatorcontrib>Vrancken, Bram</creatorcontrib><creatorcontrib>Van Houdt, Jeroen</creatorcontrib><creatorcontrib>Rajwanshi, Vivek K</creatorcontrib><creatorcontrib>Gillemot, Sarah</creatorcontrib><creatorcontrib>Andrei, Graciela</creatorcontrib><creatorcontrib>Lemey, Philippe</creatorcontrib><creatorcontrib>Naesens, Lieve</creatorcontrib><title>Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>T-705 (favipiravir) is a new antiviral agent in advanced clinical development for influenza therapy. It is supposed to act as an alternative substrate for the viral polymerase, causing inhibition of viral RNA synthesis or virus mutagenesis. These mechanisms were also proposed for ribavirin, an established and broad antiviral drug that shares structural similarity with T-705. We here performed a comparative analysis of the effects of T-705 and ribavirin on influenza virus and host cell functions. Influenza virus-infected cell cultures were exposed to T-705 or ribavirin during single or serial virus passaging. The effects on viral RNA synthesis and infectious virus yield were determined and mutations appearing in the viral genome were detected by whole-genome virus sequencing. In addition, the cellular nucleotide pools as well as direct inhibition of the viral polymerase enzyme were quantified. We demonstrate that the anti-influenza virus effect of ribavirin is based on IMP dehydrogenase inhibition, which results in fast and profound GTP depletion and an imbalance in the nucleotide pools. In contrast, T-705 acts as a potent and GTP-competitive inhibitor of the viral polymerase. In infected cells, viral RNA synthesis is completely inhibited by T-705 or ribavirin at ≥50 μM, whereas exposure to lower drug concentrations induces formation of noninfectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is 2-fold higher for T-705 than for ribavirin. Hence, T-705 and ribavirin both act as purine pseudobases but profoundly differ with regard to the mechanism behind their antiviral and mutagenic effects on influenza virus.</description><subject>A549 Cells</subject><subject>Amides</subject><subject>Amides - chemistry</subject><subject>Amides - pharmacology</subject><subject>Animals</subject><subject>Antiviral Agents</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Chick Embryo</subject><subject>DNA-Directed RNA Polymerases - antagonists & inhibitors</subject><subject>DNA-Directed RNA Polymerases - genetics</subject><subject>DNA-Directed RNA Polymerases - metabolism</subject><subject>Dogs</subject><subject>Gene Expression Regulation, Viral</subject><subject>Humans</subject><subject>IMP Dehydrogenase - antagonists & inhibitors</subject><subject>IMP Dehydrogenase - genetics</subject><subject>IMP Dehydrogenase - metabolism</subject><subject>Influenza A Virus, H1N1 Subtype</subject><subject>Influenza A Virus, H1N1 Subtype - drug effects</subject><subject>Influenza A Virus, H1N1 Subtype - genetics</subject><subject>Influenza A Virus, H1N1 Subtype - growth & development</subject><subject>Influenza A Virus, H1N1 Subtype - metabolism</subject><subject>Influenza A Virus, H3N2 Subtype</subject><subject>Influenza A Virus, H3N2 Subtype - drug effects</subject><subject>Influenza A Virus, H3N2 Subtype - genetics</subject><subject>Influenza A Virus, H3N2 Subtype - growth & development</subject><subject>Influenza A Virus, H3N2 Subtype - metabolism</subject><subject>Madin Darby Canine Kidney Cells</subject><subject>Mutation - drug effects</subject><subject>Orthomyxoviridae</subject><subject>Pyrazines</subject><subject>Pyrazines - chemistry</subject><subject>Pyrazines - pharmacology</subject><subject>Reassortant Viruses</subject><subject>Reassortant Viruses - drug effects</subject><subject>Reassortant Viruses - genetics</subject><subject>Reassortant Viruses - growth & development</subject><subject>Reassortant Viruses - metabolism</subject><subject>Ribavirin</subject><subject>Ribavirin - chemistry</subject><subject>Ribavirin - pharmacology</subject><subject>RNA, Viral - antagonists & inhibitors</subject><subject>RNA, Viral - biosynthesis</subject><subject>Sequence Analysis, RNA</subject><subject>Structure-Activity Relationship</subject><subject>Viral Proteins - antagonists & inhibitors</subject><subject>Viral Proteins - genetics</subject><subject>Viral Proteins - metabolism</subject><subject>Virus Replication - drug effects</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkd1LHDEUxYO06Gp987nkUaFj753J17wUlq1aQVrYWl9DJpOpkdnMNpkR7F9v1rViHwqFkHBzfxzOvYeQI4RTxFJ9nM8Xp4DIRYFih8wQalUIXos3ZAYgRMEUsD2yn9Id5JrXsEv2SsllWdVqRvrPPo0-2JGedZ2zY6JDR68LCZwen5t7v_Yx3_GEmtDSpW82hQ90CPQydP3kwm9Db3ycEl26de-tGX3ubeD8a3q6_Dqn3x_CeOuST-_I2870yR0-vwfkx_nZ9eJLcfXt4nIxvyoM4zgWXCrOGqMcGC47Y9EJVlc1s04ahhyEVAbAKgGqw5o1rbSOtYq3VjYNNqY6IJ-2uuupWbnWujBmL3od_crEBz0Yr__uBH-rfw73moPMp8oCx88Ccfg1uTTqlU_W9b0JbpiSRsUEAwYo_wOtaiwRkGX0wxa1cUgpuu7FEYLeZKlzlvopS40i4ydb3KRVqe-GKYa8tH-x719P_CL8J-jqEYVopgU</recordid><startdate>20161101</startdate><enddate>20161101</enddate><creator>Vanderlinden, Evelien</creator><creator>Vrancken, Bram</creator><creator>Van Houdt, Jeroen</creator><creator>Rajwanshi, Vivek K</creator><creator>Gillemot, Sarah</creator><creator>Andrei, Graciela</creator><creator>Lemey, Philippe</creator><creator>Naesens, Lieve</creator><general>American Society for Microbiology</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>7T7</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-6547-5283</orcidid></search><sort><creationdate>20161101</creationdate><title>Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis</title><author>Vanderlinden, Evelien ; Vrancken, Bram ; Van Houdt, Jeroen ; Rajwanshi, Vivek K ; Gillemot, Sarah ; Andrei, Graciela ; Lemey, Philippe ; Naesens, Lieve</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a451t-57854ba8e0a57fac1e649394ce7a4150678a00c8608f194bd7ce4d85dc7bb1ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>A549 Cells</topic><topic>Amides</topic><topic>Amides - chemistry</topic><topic>Amides - pharmacology</topic><topic>Animals</topic><topic>Antiviral Agents</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Chick Embryo</topic><topic>DNA-Directed RNA Polymerases - antagonists & inhibitors</topic><topic>DNA-Directed RNA Polymerases - genetics</topic><topic>DNA-Directed RNA Polymerases - metabolism</topic><topic>Dogs</topic><topic>Gene Expression Regulation, Viral</topic><topic>Humans</topic><topic>IMP Dehydrogenase - antagonists & inhibitors</topic><topic>IMP Dehydrogenase - genetics</topic><topic>IMP Dehydrogenase - metabolism</topic><topic>Influenza A Virus, H1N1 Subtype</topic><topic>Influenza A Virus, H1N1 Subtype - drug effects</topic><topic>Influenza A Virus, H1N1 Subtype - genetics</topic><topic>Influenza A Virus, H1N1 Subtype - growth & development</topic><topic>Influenza A Virus, H1N1 Subtype - metabolism</topic><topic>Influenza A Virus, H3N2 Subtype</topic><topic>Influenza A Virus, H3N2 Subtype - drug effects</topic><topic>Influenza A Virus, H3N2 Subtype - genetics</topic><topic>Influenza A Virus, H3N2 Subtype - growth & development</topic><topic>Influenza A Virus, H3N2 Subtype - metabolism</topic><topic>Madin Darby Canine Kidney Cells</topic><topic>Mutation - drug effects</topic><topic>Orthomyxoviridae</topic><topic>Pyrazines</topic><topic>Pyrazines - chemistry</topic><topic>Pyrazines - pharmacology</topic><topic>Reassortant Viruses</topic><topic>Reassortant Viruses - drug effects</topic><topic>Reassortant Viruses - genetics</topic><topic>Reassortant Viruses - growth & development</topic><topic>Reassortant Viruses - metabolism</topic><topic>Ribavirin</topic><topic>Ribavirin - chemistry</topic><topic>Ribavirin - pharmacology</topic><topic>RNA, Viral - antagonists & inhibitors</topic><topic>RNA, Viral - biosynthesis</topic><topic>Sequence Analysis, RNA</topic><topic>Structure-Activity Relationship</topic><topic>Viral Proteins - antagonists & inhibitors</topic><topic>Viral Proteins - genetics</topic><topic>Viral Proteins - metabolism</topic><topic>Virus Replication - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vanderlinden, Evelien</creatorcontrib><creatorcontrib>Vrancken, Bram</creatorcontrib><creatorcontrib>Van Houdt, Jeroen</creatorcontrib><creatorcontrib>Rajwanshi, Vivek K</creatorcontrib><creatorcontrib>Gillemot, Sarah</creatorcontrib><creatorcontrib>Andrei, Graciela</creatorcontrib><creatorcontrib>Lemey, Philippe</creatorcontrib><creatorcontrib>Naesens, Lieve</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Nucleic Acids Abstracts</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>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>Vanderlinden, Evelien</au><au>Vrancken, Bram</au><au>Van Houdt, Jeroen</au><au>Rajwanshi, Vivek K</au><au>Gillemot, Sarah</au><au>Andrei, Graciela</au><au>Lemey, Philippe</au><au>Naesens, Lieve</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2016-11-01</date><risdate>2016</risdate><volume>60</volume><issue>11</issue><spage>6679</spage><epage>6691</epage><pages>6679-6691</pages><issn>0066-4804</issn><eissn>1098-6596</eissn><abstract>T-705 (favipiravir) is a new antiviral agent in advanced clinical development for influenza therapy. It is supposed to act as an alternative substrate for the viral polymerase, causing inhibition of viral RNA synthesis or virus mutagenesis. These mechanisms were also proposed for ribavirin, an established and broad antiviral drug that shares structural similarity with T-705. We here performed a comparative analysis of the effects of T-705 and ribavirin on influenza virus and host cell functions. Influenza virus-infected cell cultures were exposed to T-705 or ribavirin during single or serial virus passaging. The effects on viral RNA synthesis and infectious virus yield were determined and mutations appearing in the viral genome were detected by whole-genome virus sequencing. In addition, the cellular nucleotide pools as well as direct inhibition of the viral polymerase enzyme were quantified. We demonstrate that the anti-influenza virus effect of ribavirin is based on IMP dehydrogenase inhibition, which results in fast and profound GTP depletion and an imbalance in the nucleotide pools. In contrast, T-705 acts as a potent and GTP-competitive inhibitor of the viral polymerase. In infected cells, viral RNA synthesis is completely inhibited by T-705 or ribavirin at ≥50 μM, whereas exposure to lower drug concentrations induces formation of noninfectious particles and accumulation of random point mutations in the viral genome. This mutagenic effect is 2-fold higher for T-705 than for ribavirin. Hence, T-705 and ribavirin both act as purine pseudobases but profoundly differ with regard to the mechanism behind their antiviral and mutagenic effects on influenza virus.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>27572398</pmid><doi>10.1128/AAC.01156-16</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0001-6547-5283</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | A549 Cells Amides Amides - chemistry Amides - pharmacology Animals Antiviral Agents Antiviral Agents - chemistry Antiviral Agents - pharmacology Chick Embryo DNA-Directed RNA Polymerases - antagonists & inhibitors DNA-Directed RNA Polymerases - genetics DNA-Directed RNA Polymerases - metabolism Dogs Gene Expression Regulation, Viral Humans IMP Dehydrogenase - antagonists & inhibitors IMP Dehydrogenase - genetics IMP Dehydrogenase - metabolism Influenza A Virus, H1N1 Subtype Influenza A Virus, H1N1 Subtype - drug effects Influenza A Virus, H1N1 Subtype - genetics Influenza A Virus, H1N1 Subtype - growth & development Influenza A Virus, H1N1 Subtype - metabolism Influenza A Virus, H3N2 Subtype Influenza A Virus, H3N2 Subtype - drug effects Influenza A Virus, H3N2 Subtype - genetics Influenza A Virus, H3N2 Subtype - growth & development Influenza A Virus, H3N2 Subtype - metabolism Madin Darby Canine Kidney Cells Mutation - drug effects Orthomyxoviridae Pyrazines Pyrazines - chemistry Pyrazines - pharmacology Reassortant Viruses Reassortant Viruses - drug effects Reassortant Viruses - genetics Reassortant Viruses - growth & development Reassortant Viruses - metabolism Ribavirin Ribavirin - chemistry Ribavirin - pharmacology RNA, Viral - antagonists & inhibitors RNA, Viral - biosynthesis Sequence Analysis, RNA Structure-Activity Relationship Viral Proteins - antagonists & inhibitors Viral Proteins - genetics Viral Proteins - metabolism Virus Replication - drug effects |
title | Distinct Effects of T-705 (Favipiravir) and Ribavirin on Influenza Virus Replication and Viral RNA Synthesis |
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