Interference of ribosomal frameshifting by antisense peptide nucleic acids suppresses SARS coronavirus replication
Identifieur interne : 002368 ( Main/Exploration ); précédent : 002367; suivant : 002369Interference of ribosomal frameshifting by antisense peptide nucleic acids suppresses SARS coronavirus replication
Auteurs : Dae-Gyun Ahn [Corée du Sud] ; Wooseong Lee [Corée du Sud] ; Jin-Kyu Choi [Corée du Sud] ; Seong-Jun Kim [Corée du Sud] ; Ewan P. Plant [États-Unis] ; Fernando Almazan [Espagne] ; Deborah R. Taylor [États-Unis] ; Luis Enjuanes [Espagne] ; Jong-Won Oh [Corée du Sud]Source :
- Antiviral research [ 0166-3542 ] ; 2011.
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Abstract
The programmed -1 ribosomal frameshifting (-1 PRF) utilized by eukaryotic RNA viruses plays a crucial role for the controlled, limited synthesis of viral RNA replicase polyproteins required for genome replication. The viral RNA replicase polyproteins of severe acute respiratory syndrome coronavirus (SARS-CoV) are encoded by the two overlapping open reading frames 1 a and 1 b, which are connected by a -1 PRF signal. We evaluated the antiviral effects of antisense peptide nucleic acids (PNAs) targeting a highly conserved RNA sequence on the - PRF signal. The ribosomal frameshifting was inhibited by the PNA, which bound sequence-specifically a pseudoknot structure in the -1 PRF signal, in cell lines as assessed using a dual luciferase-based reporter plasmid containing the -1 PRF signal. Treatment of cells, which were transfected with a SARS-CoV-replicon expressing firefly luciferase, with the PNA fused to a cell-penetrating peptide (CPP) resulted in suppression of the replication of the SARS-CoV replicon, with a 50% inhibitory concentration of 4.4 μM. There was no induction of type I interferon responses by PNA treatment, suggesting that the effect of PNA is not due to innate immune responses. Our results demonstrate that -1 PRF, critical for SARS-CoV viral replication, can be inhibited by CPP-PNA, providing an effective antisense strategy for blocking -1 PRF signals.
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Taylor</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Laboratory of Hepatitis and Related Emerging Agents, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Cell and Molecular Biology, Centro Nacional de Biotecnologia, CSIC, Campus Universidad Autónoma, Cantoblanco, C/Darwin 3</s1><s2>28049 Madrid</s2><s3>ESP</s3><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Espagne</country><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Oh, Jong Won" sort="Oh, Jong Won" uniqKey="Oh J" first="Jong-Won" last="Oh">Jong-Won Oh</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Biotechnology and Translational Research Center for Protein Function Control, Yonsei University</s1><s2>Seoul 120-749</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Corée du Sud</country><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">11-0420570</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 11-0420570 INIST</idno><idno type="RBID">Pascal:11-0420570</idno><idno type="wicri:Area/PascalFrancis/Corpus">000091</idno><idno type="wicri:Area/PascalFrancis/Curation">000897</idno><idno 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aut.</sZ></inist:fA14><country>Corée du Sud</country><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Lee, Wooseong" sort="Lee, Wooseong" uniqKey="Lee W" first="Wooseong" last="Lee">Wooseong Lee</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Biotechnology and Translational Research Center for Protein Function Control, Yonsei University</s1><s2>Seoul 120-749</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Corée du Sud</country><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Choi, Jin Kyu" sort="Choi, Jin Kyu" uniqKey="Choi J" first="Jin-Kyu" last="Choi">Jin-Kyu Choi</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Biotechnology and Translational Research Center for Protein Function Control, Yonsei University</s1><s2>Seoul 120-749</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Corée du Sud</country><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Kim, Seong Jun" sort="Kim, Seong Jun" uniqKey="Kim S" first="Seong-Jun" last="Kim">Seong-Jun Kim</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Biotechnology and Translational Research Center for Protein Function Control, Yonsei University</s1><s2>Seoul 120-749</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Corée du Sud</country><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author><author><name sortKey="Plant, Ewan P" sort="Plant, Ewan P" uniqKey="Plant E" first="Ewan P." last="Plant">Ewan P. Plant</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Laboratory of Hepatitis and Related Emerging Agents, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Almazan, Fernando" sort="Almazan, Fernando" uniqKey="Almazan F" first="Fernando" last="Almazan">Fernando Almazan</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Cell and Molecular Biology, Centro Nacional de Biotecnologia, CSIC, Campus Universidad Autónoma, Cantoblanco, C/Darwin 3</s1><s2>28049 Madrid</s2><s3>ESP</s3><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Espagne</country><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Taylor, Deborah R" sort="Taylor, Deborah R" uniqKey="Taylor D" first="Deborah R." last="Taylor">Deborah R. Taylor</name><affiliation wicri:level="2"><inist:fA14 i1="02"><s1>Laboratory of Hepatitis and Related Emerging Agents, Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration</s1><s2>Bethesda, MD</s2><s3>USA</s3><sZ>5 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><affiliation wicri:level="2"><inist:fA14 i1="03"><s1>Department of Cell and Molecular Biology, Centro Nacional de Biotecnologia, CSIC, Campus Universidad Autónoma, Cantoblanco, C/Darwin 3</s1><s2>28049 Madrid</s2><s3>ESP</s3><sZ>6 aut.</sZ><sZ>8 aut.</sZ></inist:fA14><country>Espagne</country><placeName><region nuts="2" type="communauté">Communauté de Madrid</region></placeName></affiliation></author><author><name sortKey="Oh, Jong Won" sort="Oh, Jong Won" uniqKey="Oh J" first="Jong-Won" last="Oh">Jong-Won Oh</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Department of Biotechnology and Translational Research Center for Protein Function Control, Yonsei University</s1><s2>Seoul 120-749</s2><s3>KOR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>9 aut.</sZ></inist:fA14><country>Corée du Sud</country><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation></author></analytic><series><title level="j" type="main">Antiviral research</title><title level="j" type="abbreviated">Antivir. res.</title><idno type="ISSN">0166-3542</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Antiviral research</title><title level="j" type="abbreviated">Antivir. res.</title><idno type="ISSN">0166-3542</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antisense oligonucleotide</term><term>Antiviral</term><term>Peptide nucleic acid</term><term>RNA</term><term>Replication</term><term>Severe acute respiratory syndrome virus</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Acide peptide nucléique</term><term>Virus syndrome respiratoire aigu sévère</term><term>Réplication</term><term>RNA</term><term>Oligonucléotide antisens</term><term>Antiviral</term><term>Décalage cadre lecture</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The programmed -1 ribosomal frameshifting (-1 PRF) utilized by eukaryotic RNA viruses plays a crucial role for the controlled, limited synthesis of viral RNA replicase polyproteins required for genome replication. The viral RNA replicase polyproteins of severe acute respiratory syndrome coronavirus (SARS-CoV) are encoded by the two overlapping open reading frames 1 a and 1 b, which are connected by a -1 PRF signal. We evaluated the antiviral effects of antisense peptide nucleic acids (PNAs) targeting a highly conserved RNA sequence on the - PRF signal. The ribosomal frameshifting was inhibited by the PNA, which bound sequence-specifically a pseudoknot structure in the -1 PRF signal, in cell lines as assessed using a dual luciferase-based reporter plasmid containing the -1 PRF signal. Treatment of cells, which were transfected with a SARS-CoV-replicon expressing firefly luciferase, with the PNA fused to a cell-penetrating peptide (CPP) resulted in suppression of the replication of the SARS-CoV replicon, with a 50% inhibitory concentration of 4.4 μM. There was no induction of type I interferon responses by PNA treatment, suggesting that the effect of PNA is not due to innate immune responses. Our results demonstrate that -1 PRF, critical for SARS-CoV viral replication, can be inhibited by CPP-PNA, providing an effective antisense strategy for blocking -1 PRF signals.</div></front></TEI><affiliations><list><country><li>Corée du Sud</li><li>Espagne</li><li>États-Unis</li></country><region><li>Communauté de Madrid</li><li>Maryland</li><li>Région capitale de Séoul</li></region><settlement><li>Séoul</li></settlement></list><tree><country name="Corée du Sud"><region name="Région capitale de Séoul"><name sortKey="Ahn, Dae Gyun" sort="Ahn, Dae Gyun" uniqKey="Ahn D" first="Dae-Gyun" last="Ahn">Dae-Gyun Ahn</name></region><name sortKey="Choi, Jin Kyu" sort="Choi, Jin Kyu" uniqKey="Choi J" first="Jin-Kyu" last="Choi">Jin-Kyu Choi</name><name sortKey="Kim, Seong Jun" sort="Kim, Seong Jun" uniqKey="Kim S" first="Seong-Jun" last="Kim">Seong-Jun Kim</name><name sortKey="Lee, Wooseong" sort="Lee, Wooseong" uniqKey="Lee W" first="Wooseong" last="Lee">Wooseong Lee</name><name sortKey="Oh, Jong Won" sort="Oh, Jong Won" uniqKey="Oh J" first="Jong-Won" last="Oh">Jong-Won Oh</name></country><country name="États-Unis"><region name="Maryland"><name sortKey="Plant, Ewan P" sort="Plant, Ewan P" uniqKey="Plant E" first="Ewan P." last="Plant">Ewan P. Plant</name></region><name sortKey="Taylor, Deborah R" sort="Taylor, Deborah R" uniqKey="Taylor D" first="Deborah R." last="Taylor">Deborah R. Taylor</name></country><country name="Espagne"><region name="Communauté de Madrid"><name sortKey="Almazan, Fernando" sort="Almazan, Fernando" uniqKey="Almazan F" first="Fernando" last="Almazan">Fernando Almazan</name></region><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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