Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting
Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a programmed −1 ribosomal frameshift (−1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2021-06, Vol.118 (26), p.1-7 |
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| creator | Sun, Yu Abriola, Laura Niederer, Rachel O. Pedersen, Savannah F. Alfajaro, Mia M. Monteiro, Valter Silva Wilen, Craig B. Ho, Ya-Chi Gilbert, Wendy V. Surovtseva, Yulia V. Lindenbach, Brett D. Guo, Junjie U. |
| description | Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a programmed −1 ribosomal frameshift (−1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a −1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on −1 PRF of other betacoronaviruses. Consistent with the essential role of −1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting −1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses. |
| doi_str_mv | 10.1073/pnas.2023051118 |
| format | Article |
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The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a −1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on −1 PRF of other betacoronaviruses. Consistent with the essential role of −1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting −1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2023051118</identifier><identifier>PMID: 34185680</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Antiinfectives and antibacterials ; Antiviral Agents - pharmacology ; Betacoronavirus ; Biological Sciences ; Chlorocebus aethiops ; Coronaviruses ; Fluoroquinolones - pharmacology ; Frameshifting, Ribosomal - drug effects ; Frameshifting, Ribosomal - genetics ; Gene expression ; Mutation ; Nucleic Acid Conformation ; Replication ; RNA, Viral - chemistry ; RNA, Viral - genetics ; SARS-CoV-2 - drug effects ; SARS-CoV-2 - physiology ; Severe acute respiratory syndrome ; Severe acute respiratory syndrome coronavirus 2 ; Vero Cells ; Viral diseases ; Virus Replication - drug effects</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-06, Vol.118 (26), p.1-7</ispartof><rights>Copyright © 2021 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Jun 29, 2021</rights><rights>Copyright © 2021 the Author(s). Published by PNAS. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-373a9650e7c92d6ace4f69dcd4aa8239ae0ea377bf9ea19419f5d2c2b7f440193</citedby><cites>FETCH-LOGICAL-c443t-373a9650e7c92d6ace4f69dcd4aa8239ae0ea377bf9ea19419f5d2c2b7f440193</cites><orcidid>0000-0002-3091-903X ; 0000-0003-4191-1786 ; 0000-0001-8871-0055 ; 0000-0003-1785-6713 ; 0000-0003-2807-9657 ; 0000-0002-7304-6531 ; 0000-0003-2495-9403</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27040946$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27040946$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27915,27916,53782,53784,58008,58241</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34185680$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Yu</creatorcontrib><creatorcontrib>Abriola, Laura</creatorcontrib><creatorcontrib>Niederer, Rachel O.</creatorcontrib><creatorcontrib>Pedersen, Savannah F.</creatorcontrib><creatorcontrib>Alfajaro, Mia M.</creatorcontrib><creatorcontrib>Monteiro, Valter Silva</creatorcontrib><creatorcontrib>Wilen, Craig B.</creatorcontrib><creatorcontrib>Ho, Ya-Chi</creatorcontrib><creatorcontrib>Gilbert, Wendy V.</creatorcontrib><creatorcontrib>Surovtseva, Yulia V.</creatorcontrib><creatorcontrib>Lindenbach, Brett D.</creatorcontrib><creatorcontrib>Guo, Junjie U.</creatorcontrib><title>Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a programmed −1 ribosomal frameshift (−1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a −1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on −1 PRF of other betacoronaviruses. Consistent with the essential role of −1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting −1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses.</description><subject>Animals</subject><subject>Antiinfectives and antibacterials</subject><subject>Antiviral Agents - pharmacology</subject><subject>Betacoronavirus</subject><subject>Biological Sciences</subject><subject>Chlorocebus aethiops</subject><subject>Coronaviruses</subject><subject>Fluoroquinolones - pharmacology</subject><subject>Frameshifting, Ribosomal - drug effects</subject><subject>Frameshifting, Ribosomal - genetics</subject><subject>Gene expression</subject><subject>Mutation</subject><subject>Nucleic Acid Conformation</subject><subject>Replication</subject><subject>RNA, Viral - chemistry</subject><subject>RNA, Viral - genetics</subject><subject>SARS-CoV-2 - drug effects</subject><subject>SARS-CoV-2 - physiology</subject><subject>Severe acute respiratory syndrome</subject><subject>Severe acute respiratory syndrome coronavirus 2</subject><subject>Vero Cells</subject><subject>Viral diseases</subject><subject>Virus Replication - drug effects</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkU1P3DAQhq2qCLaUMyeqSFy4BMYfseNLJbSCFgkJCVoOXCzHsRevkji1s0j8g577E_tL6u3C9uM00rzPvJqZF6FDDKcYBD0bB51OCRAKFca4foNmGCQuOZPwFs0AiChrRtgeepfSEgBkVcMu2qMM1xWvYYYebm2aojeTD0MRXHF3fntXzsN9SYpox84b_VtpnotJx4Wd_LAoxhgWUfe9bYuf33_gIvompNDrrnC5bdOjd2vuPdpxukv24KXuo6-XF1_mn8vrm09X8_Pr0jBGp5IKqiWvwAojScu1scxx2ZqWaV0TKrUFq6kQjZNWY8mwdFVLDGmEYwywpPvo48Z3XDV5J2OHKepOjdH3Oj6roL36Vxn8o1qEJ1WTigOFbHDyYhDDt1X-h-p9Mrbr9GDDKilSMS5FhTnL6PF_6DKs4pDPW1NSEIElydTZhjIxpBSt2y6DQa1zU-vc1J_c8sSHv2_Y8q9BZeBoAyzTFOJWJwIYSMbpLy92n3U</recordid><startdate>20210629</startdate><enddate>20210629</enddate><creator>Sun, Yu</creator><creator>Abriola, Laura</creator><creator>Niederer, Rachel O.</creator><creator>Pedersen, Savannah F.</creator><creator>Alfajaro, Mia M.</creator><creator>Monteiro, Valter Silva</creator><creator>Wilen, Craig B.</creator><creator>Ho, Ya-Chi</creator><creator>Gilbert, Wendy V.</creator><creator>Surovtseva, Yulia V.</creator><creator>Lindenbach, Brett D.</creator><creator>Guo, Junjie U.</creator><general>National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-3091-903X</orcidid><orcidid>https://orcid.org/0000-0003-4191-1786</orcidid><orcidid>https://orcid.org/0000-0001-8871-0055</orcidid><orcidid>https://orcid.org/0000-0003-1785-6713</orcidid><orcidid>https://orcid.org/0000-0003-2807-9657</orcidid><orcidid>https://orcid.org/0000-0002-7304-6531</orcidid><orcidid>https://orcid.org/0000-0003-2495-9403</orcidid></search><sort><creationdate>20210629</creationdate><title>Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting</title><author>Sun, Yu ; 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The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a −1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on −1 PRF of other betacoronaviruses. Consistent with the essential role of −1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting −1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>34185680</pmid><doi>10.1073/pnas.2023051118</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0002-3091-903X</orcidid><orcidid>https://orcid.org/0000-0003-4191-1786</orcidid><orcidid>https://orcid.org/0000-0001-8871-0055</orcidid><orcidid>https://orcid.org/0000-0003-1785-6713</orcidid><orcidid>https://orcid.org/0000-0003-2807-9657</orcidid><orcidid>https://orcid.org/0000-0002-7304-6531</orcidid><orcidid>https://orcid.org/0000-0003-2495-9403</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antiinfectives and antibacterials Antiviral Agents - pharmacology Betacoronavirus Biological Sciences Chlorocebus aethiops Coronaviruses Fluoroquinolones - pharmacology Frameshifting, Ribosomal - drug effects Frameshifting, Ribosomal - genetics Gene expression Mutation Nucleic Acid Conformation Replication RNA, Viral - chemistry RNA, Viral - genetics SARS-CoV-2 - drug effects SARS-CoV-2 - physiology Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Vero Cells Viral diseases Virus Replication - drug effects |
| title | Restriction of SARS-CoV-2 replication by targeting programmed −1 ribosomal frameshifting |
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