A cell-based assay to discover inhibitors of Zika virus RNA-dependent RNA polymerase
Zika virus (ZIKV) belongs to Flaviviridae, the Flavivirus genus. Its infection causes congenital brain abnormalities and Guillain–Barré syndrome. However, there are no effective vaccines, no FDA-approved drugs to manage ZIKV infection. The non-structural protein NS5 of ZIKV has been recognized as a...
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| Veröffentlicht in: | Virology (New York, N.Y.) N.Y.), 2024-01, Vol.589, p.109939-109939, Article 109939 |
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| container_title | Virology (New York, N.Y.) |
| container_volume | 589 |
| creator | Wang, Lidan Zhou, Rui Liu, Yitong Guo, Saisai Yi, Dongrong Zhao, Jianyuan Li, Quanjie Zhang, Yongxin Liang, Chen Wang, Jing Shan, Guangzhi Cen, Shan |
| description | Zika virus (ZIKV) belongs to Flaviviridae, the Flavivirus genus. Its infection causes congenital brain abnormalities and Guillain–Barré syndrome. However, there are no effective vaccines, no FDA-approved drugs to manage ZIKV infection. The non-structural protein NS5 of ZIKV has been recognized as a valuable target of antivirals because of its RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase) activities essential for viral RNA synthesis. Here, we report a cell-based assay for discovering inhibitors of ZIKV NS5 and found that 5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 μM. Furthermore, 5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription. Therefore, we have developed a cell-based ZIKV NS5 assay which can be deployed to discover ZIKV NS5 inhibitors and demonstrated the potential of 5-Azacytidine for further development as a ZIKV NS5 inhibitor.
•A cell-based assay for discovering inhibitors of ZIKV NS5 is established.•5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 μM.•5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription. |
| doi_str_mv | 10.1016/j.virol.2023.109939 |
| format | Article |
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•A cell-based assay for discovering inhibitors of ZIKV NS5 is established.•5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 μM.•5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription.</description><identifier>ISSN: 0042-6822</identifier><identifier>EISSN: 1096-0341</identifier><identifier>DOI: 10.1016/j.virol.2023.109939</identifier><identifier>PMID: 37979208</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>5-Azacytidine ; Antiviral ; antiviral agents ; Antiviral Agents - chemistry ; Azacitidine - metabolism ; Azacitidine - pharmacology ; Azacitidine - therapeutic use ; brain ; genus ; Humans ; methyltransferases ; NS5 ; Nucleotide analog inhibitor ; RNA ; RNA, Viral - genetics ; RNA, Viral - metabolism ; RNA-Dependent RNA Polymerase - metabolism ; RNA-directed RNA polymerase ; viral nonstructural proteins ; Viral Nonstructural Proteins - metabolism ; virology ; Virus Replication ; Zika virus ; Zika Virus - genetics ; Zika Virus Infection - drug therapy ; ZIKV</subject><ispartof>Virology (New York, N.Y.), 2024-01, Vol.589, p.109939-109939, Article 109939</ispartof><rights>2023 Elsevier Inc.</rights><rights>Copyright © 2023 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c392t-261a11e78ba667741b1bd526b36c328b403050861df37d299cbecd095e114f693</citedby><cites>FETCH-LOGICAL-c392t-261a11e78ba667741b1bd526b36c328b403050861df37d299cbecd095e114f693</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.virol.2023.109939$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,778,782,3539,27907,27908,45978</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37979208$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wang, Lidan</creatorcontrib><creatorcontrib>Zhou, Rui</creatorcontrib><creatorcontrib>Liu, Yitong</creatorcontrib><creatorcontrib>Guo, Saisai</creatorcontrib><creatorcontrib>Yi, Dongrong</creatorcontrib><creatorcontrib>Zhao, Jianyuan</creatorcontrib><creatorcontrib>Li, Quanjie</creatorcontrib><creatorcontrib>Zhang, Yongxin</creatorcontrib><creatorcontrib>Liang, Chen</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Shan, Guangzhi</creatorcontrib><creatorcontrib>Cen, Shan</creatorcontrib><title>A cell-based assay to discover inhibitors of Zika virus RNA-dependent RNA polymerase</title><title>Virology (New York, N.Y.)</title><addtitle>Virology</addtitle><description>Zika virus (ZIKV) belongs to Flaviviridae, the Flavivirus genus. Its infection causes congenital brain abnormalities and Guillain–Barré syndrome. However, there are no effective vaccines, no FDA-approved drugs to manage ZIKV infection. The non-structural protein NS5 of ZIKV has been recognized as a valuable target of antivirals because of its RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase) activities essential for viral RNA synthesis. Here, we report a cell-based assay for discovering inhibitors of ZIKV NS5 and found that 5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 μM. Furthermore, 5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription. Therefore, we have developed a cell-based ZIKV NS5 assay which can be deployed to discover ZIKV NS5 inhibitors and demonstrated the potential of 5-Azacytidine for further development as a ZIKV NS5 inhibitor.
•A cell-based assay for discovering inhibitors of ZIKV NS5 is established.•5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 μM.•5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription.</description><subject>5-Azacytidine</subject><subject>Antiviral</subject><subject>antiviral agents</subject><subject>Antiviral Agents - chemistry</subject><subject>Azacitidine - metabolism</subject><subject>Azacitidine - pharmacology</subject><subject>Azacitidine - therapeutic use</subject><subject>brain</subject><subject>genus</subject><subject>Humans</subject><subject>methyltransferases</subject><subject>NS5</subject><subject>Nucleotide analog inhibitor</subject><subject>RNA</subject><subject>RNA, Viral - genetics</subject><subject>RNA, Viral - metabolism</subject><subject>RNA-Dependent RNA Polymerase - metabolism</subject><subject>RNA-directed RNA polymerase</subject><subject>viral nonstructural proteins</subject><subject>Viral Nonstructural Proteins - metabolism</subject><subject>virology</subject><subject>Virus Replication</subject><subject>Zika virus</subject><subject>Zika Virus - genetics</subject><subject>Zika Virus Infection - drug therapy</subject><subject>ZIKV</subject><issn>0042-6822</issn><issn>1096-0341</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkE1PGzEQhq2qqKS0v6BS5WMvm3rsjb0-cIgQUCQEEqKXXix_zKpON-tgbyLl3-MQ2iM92WM9M-_4IeQLsDkwkN9X813MaZhzxkV90Vrod2RWL7JhooX3ZMZYyxvZcX5KPpayYrVWin0gp0JppTnrZuRxST0OQ-NswUBtKXZPp0RDLD7tMNM4_o4uTikXmnr6K_6xtKZuC324WzYBNzgGHKdDRTdp2K8x10GfyElvh4KfX88z8vPq8vHiR3N7f31zsbxtvNB8argEC4Cqc1ZKpVpw4MKCSyekF7xzLRNswToJoRcqcK29Qx-YXiBA20stzsi349xNTk9bLJNZ173rd-yIaVuMgIXooGXA_4vyToNqdZVVUXFEfU6lZOzNJse1zXsDzBzMm5V5MW8O5s3RfO36-hqwdWsM_3r-qq7A-RHAamQXMZviI44eQ8zoJxNSfDPgGfT9k6U</recordid><startdate>202401</startdate><enddate>202401</enddate><creator>Wang, Lidan</creator><creator>Zhou, Rui</creator><creator>Liu, Yitong</creator><creator>Guo, Saisai</creator><creator>Yi, Dongrong</creator><creator>Zhao, Jianyuan</creator><creator>Li, Quanjie</creator><creator>Zhang, Yongxin</creator><creator>Liang, Chen</creator><creator>Wang, Jing</creator><creator>Shan, Guangzhi</creator><creator>Cen, Shan</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7X8</scope><scope>7S9</scope><scope>L.6</scope></search><sort><creationdate>202401</creationdate><title>A cell-based assay to discover inhibitors of Zika virus RNA-dependent RNA polymerase</title><author>Wang, Lidan ; Zhou, Rui ; Liu, Yitong ; Guo, Saisai ; Yi, Dongrong ; Zhao, Jianyuan ; Li, Quanjie ; Zhang, Yongxin ; Liang, Chen ; Wang, Jing ; Shan, Guangzhi ; Cen, Shan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c392t-261a11e78ba667741b1bd526b36c328b403050861df37d299cbecd095e114f693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>5-Azacytidine</topic><topic>Antiviral</topic><topic>antiviral agents</topic><topic>Antiviral Agents - chemistry</topic><topic>Azacitidine - metabolism</topic><topic>Azacitidine - pharmacology</topic><topic>Azacitidine - therapeutic use</topic><topic>brain</topic><topic>genus</topic><topic>Humans</topic><topic>methyltransferases</topic><topic>NS5</topic><topic>Nucleotide analog inhibitor</topic><topic>RNA</topic><topic>RNA, Viral - genetics</topic><topic>RNA, Viral - metabolism</topic><topic>RNA-Dependent RNA Polymerase - metabolism</topic><topic>RNA-directed RNA polymerase</topic><topic>viral nonstructural proteins</topic><topic>Viral Nonstructural Proteins - metabolism</topic><topic>virology</topic><topic>Virus Replication</topic><topic>Zika virus</topic><topic>Zika Virus - genetics</topic><topic>Zika Virus Infection - drug therapy</topic><topic>ZIKV</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Lidan</creatorcontrib><creatorcontrib>Zhou, Rui</creatorcontrib><creatorcontrib>Liu, Yitong</creatorcontrib><creatorcontrib>Guo, Saisai</creatorcontrib><creatorcontrib>Yi, Dongrong</creatorcontrib><creatorcontrib>Zhao, Jianyuan</creatorcontrib><creatorcontrib>Li, Quanjie</creatorcontrib><creatorcontrib>Zhang, Yongxin</creatorcontrib><creatorcontrib>Liang, Chen</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Shan, Guangzhi</creatorcontrib><creatorcontrib>Cen, Shan</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><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>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Virology (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Lidan</au><au>Zhou, Rui</au><au>Liu, Yitong</au><au>Guo, Saisai</au><au>Yi, Dongrong</au><au>Zhao, Jianyuan</au><au>Li, Quanjie</au><au>Zhang, Yongxin</au><au>Liang, Chen</au><au>Wang, Jing</au><au>Shan, Guangzhi</au><au>Cen, Shan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A cell-based assay to discover inhibitors of Zika virus RNA-dependent RNA polymerase</atitle><jtitle>Virology (New York, N.Y.)</jtitle><addtitle>Virology</addtitle><date>2024-01</date><risdate>2024</risdate><volume>589</volume><spage>109939</spage><epage>109939</epage><pages>109939-109939</pages><artnum>109939</artnum><issn>0042-6822</issn><eissn>1096-0341</eissn><abstract>Zika virus (ZIKV) belongs to Flaviviridae, the Flavivirus genus. Its infection causes congenital brain abnormalities and Guillain–Barré syndrome. However, there are no effective vaccines, no FDA-approved drugs to manage ZIKV infection. The non-structural protein NS5 of ZIKV has been recognized as a valuable target of antivirals because of its RNA-dependent RNA polymerase (RdRp) and methyltransferase (MTase) activities essential for viral RNA synthesis. Here, we report a cell-based assay for discovering inhibitors of ZIKV NS5 and found that 5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 μM. Furthermore, 5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription. Therefore, we have developed a cell-based ZIKV NS5 assay which can be deployed to discover ZIKV NS5 inhibitors and demonstrated the potential of 5-Azacytidine for further development as a ZIKV NS5 inhibitor.
•A cell-based assay for discovering inhibitors of ZIKV NS5 is established.•5-Azacytidine potently inhibits ZIKV NS5, with EC50 of 4.9 μM.•5-Azacytidine suppresses ZIKV replication by inhibiting NS5-mediated viral RNA transcription.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>37979208</pmid><doi>10.1016/j.virol.2023.109939</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Virology (New York, N.Y.), 2024-01, Vol.589, p.109939-109939, Article 109939 |
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| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals |
| subjects | 5-Azacytidine Antiviral antiviral agents Antiviral Agents - chemistry Azacitidine - metabolism Azacitidine - pharmacology Azacitidine - therapeutic use brain genus Humans methyltransferases NS5 Nucleotide analog inhibitor RNA RNA, Viral - genetics RNA, Viral - metabolism RNA-Dependent RNA Polymerase - metabolism RNA-directed RNA polymerase viral nonstructural proteins Viral Nonstructural Proteins - metabolism virology Virus Replication Zika virus Zika Virus - genetics Zika Virus Infection - drug therapy ZIKV |
| title | A cell-based assay to discover inhibitors of Zika virus RNA-dependent RNA polymerase |
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