Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion
SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2022-03, Vol.119 (9), p.1-10 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Vora, Setu M. Fontana, Pietro Mao, Tianyang Leger, Valerie Zhang, Ying Fu, Tian-Min Lieberman, Judy Gehrke, Lee Shi, Ming Wang, Longfei Iwasaki, Akiko Wu, Hao |
| description | SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5′ untranslated region (5′ UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5′ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2–induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus’ own virulence mechanism against itself could force a critical trade-off between drug resistance and pathogenicity. |
| doi_str_mv | 10.1073/pnas.2117198119 |
| format | Article |
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The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5′ untranslated region (5′ UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5′ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2–induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus’ own virulence mechanism against itself could force a critical trade-off between drug resistance and pathogenicity.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2117198119</identifier><identifier>PMID: 35149555</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>5' Untranslated Regions ; 5' Untranslated Regions - genetics ; ACE2 ; Angiotensin-converting enzyme 2 ; Animals ; Antisense oligonucleotides ; Antisense therapy ; Base Sequence ; Biological Sciences ; Chlorocebus aethiops ; COVID-19 ; Drug resistance ; HEK293 Cells ; Host-Pathogen Interactions - drug effects ; Host-Pathogen Interactions - genetics ; Humans ; Immune Evasion - drug effects ; Immune Evasion - genetics ; Lethality ; Mice, Transgenic ; Models, Biological ; mRNA stability ; Nucleic acids ; Oligonucleotides ; Oligonucleotides, Antisense - pharmacology ; Pathogenicity ; Pathogens ; Protein biosynthesis ; Protein Biosynthesis - drug effects ; Protein synthesis ; Protein transport ; Proteins ; Replication ; SARS-CoV-2 - drug effects ; SARS-CoV-2 - genetics ; Severe acute respiratory syndrome coronavirus 2 ; Therapeutic targets ; Transcription ; Transgenic mice ; Translation ; Vero Cells ; Viral diseases ; Viral Nonstructural Proteins - genetics ; Virulence ; Virus Replication - drug effects ; Viruses</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2022-03, Vol.119 (9), p.1-10</ispartof><rights>Copyright © 2022 the Author(s). Published by PNAS.</rights><rights>Copyright National Academy of Sciences Mar 1, 2022</rights><rights>Copyright © 2022 the Author(s). Published by PNAS. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-2a370e2ca2058db9bd846ae312c02c7e2b956f4d9d34f789250dd1e984ad52373</citedby><cites>FETCH-LOGICAL-c443t-2a370e2ca2058db9bd846ae312c02c7e2b956f4d9d34f789250dd1e984ad52373</cites><orcidid>0000-0002-7824-9856 ; 0000-0002-1116-2182 ; 0000-0002-9387-8212 ; 0000-0002-7281-8579 ; 0000-0003-0527-0061 ; 0000-0002-6281-1752</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/PMC8892331/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8892331/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35149555$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vora, Setu M.</creatorcontrib><creatorcontrib>Fontana, Pietro</creatorcontrib><creatorcontrib>Mao, Tianyang</creatorcontrib><creatorcontrib>Leger, Valerie</creatorcontrib><creatorcontrib>Zhang, Ying</creatorcontrib><creatorcontrib>Fu, Tian-Min</creatorcontrib><creatorcontrib>Lieberman, Judy</creatorcontrib><creatorcontrib>Gehrke, Lee</creatorcontrib><creatorcontrib>Shi, Ming</creatorcontrib><creatorcontrib>Wang, Longfei</creatorcontrib><creatorcontrib>Iwasaki, Akiko</creatorcontrib><creatorcontrib>Wu, Hao</creatorcontrib><title>Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5′ untranslated region (5′ UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5′ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2–induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. 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PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vora, Setu M.</au><au>Fontana, Pietro</au><au>Mao, Tianyang</au><au>Leger, Valerie</au><au>Zhang, Ying</au><au>Fu, Tian-Min</au><au>Lieberman, Judy</au><au>Gehrke, Lee</au><au>Shi, Ming</au><au>Wang, Longfei</au><au>Iwasaki, Akiko</au><au>Wu, Hao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2022-03-01</date><risdate>2022</risdate><volume>119</volume><issue>9</issue><spage>1</spage><epage>10</epage><pages>1-10</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>SARS-CoV-2 is a highly pathogenic virus that evades antiviral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the messenger RNA (mRNA) entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here, we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the stem-loop 1 (SL1) region of the SARS-CoV-2 5′ untranslated region (5′ UTR) is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides inhibits viral translation and makes SARS-CoV-2 5′ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration, as well as providing protection against SARS-CoV-2–induced lethality in transgenic mice expressing human ACE2. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. 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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2022-03, Vol.119 (9), p.1-10 |
| issn | 0027-8424 1091-6490 |
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| source | MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | 5' Untranslated Regions 5' Untranslated Regions - genetics ACE2 Angiotensin-converting enzyme 2 Animals Antisense oligonucleotides Antisense therapy Base Sequence Biological Sciences Chlorocebus aethiops COVID-19 Drug resistance HEK293 Cells Host-Pathogen Interactions - drug effects Host-Pathogen Interactions - genetics Humans Immune Evasion - drug effects Immune Evasion - genetics Lethality Mice, Transgenic Models, Biological mRNA stability Nucleic acids Oligonucleotides Oligonucleotides, Antisense - pharmacology Pathogenicity Pathogens Protein biosynthesis Protein Biosynthesis - drug effects Protein synthesis Protein transport Proteins Replication SARS-CoV-2 - drug effects SARS-CoV-2 - genetics Severe acute respiratory syndrome coronavirus 2 Therapeutic targets Transcription Transgenic mice Translation Vero Cells Viral diseases Viral Nonstructural Proteins - genetics Virulence Virus Replication - drug effects Viruses |
| title | Targeting stem-loop 1 of the SARS-CoV-2 5′ UTR to suppress viral translation and Nsp1 evasion |
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