Severe Acute Respiratory Syndrome Coronavirus Replication Inhibitor That Interferes with the Nucleic Acid Unwinding of the Viral Helicase
Identifieur interne : 000938 ( PascalFrancis/Curation ); précédent : 000937; suivant : 000939Severe Acute Respiratory Syndrome Coronavirus Replication Inhibitor That Interferes with the Nucleic Acid Unwinding of the Viral Helicase
Auteurs : Adeyemi O. Adedeji [États-Unis] ; Kamalendra Singh [États-Unis] ; Nicholas E. Calcaterra [États-Unis] ; Marta L. Dediego [Espagne] ; Luis Enjuanes [Espagne] ; Susan Weiss [États-Unis] ; Stefan G. Sarafianos [États-Unis]Source :
- Antimicrobial agents and chemotherapy [ 0066-4804 ] ; 2012.
Descripteurs français
- Pascal (Inist)
English descriptors
Abstract
Severe acute respiratory syndrome (SARS) is a highly contagious disease, caused by SARS coronavirus (SARS-CoV), for which there are no approved treatments. We report the discovery of a potent inhibitor of SARS-CoV that blocks replication by inhibiting the unwinding activity of the SARS-CoV helicase (nsp13). We used a Förster resonance energy transfer (FRET)-based helicase assay to screen the Maybridge Hitfinder chemical library. We identified and validated a compound (SSYA10-001) that specifically blocks the double-stranded RNA (dsRNA) and dsDNA unwinding activities of nsp13, with 50% inhibitory concentrations (IC50s) of 5.70 and 5.30 μM, respectively. This compound also has inhibitory activity (50% effective concentration [EC50] = 8.95 μM) in a SARS-CoV replicon assay, with low cytotoxicity (50% cytotoxic concentration [CC50] = >250 μM), suggesting that the helicase plays a still unidentified critical role in the SARS-CoV life cycle. Enzyme kinetic studies on the mechanism of nsp13 inhibition revealed that SSYA10-001 acts as a noncompetitive inhibitor of nsp13 with respect to nucleic acid and ATP substrates. Moreover, SSYA10-001 does not affect ATP hydrolysis or nsp13 binding to the nucleic acid substrate. SSYA10-001 did not inhibit hepatitis C virus (HCV) helicase, other bacterial and viral RNA-dependent RNA polymerases, or reverse transcriptase. These results suggest that SSYA10-001 specifically blocks nsp13 through a novel mechanism and is less likely to interfere with the functions of cellular enzymes that process nucleic acids or ATP. Hence, it is possible that SSYA10-001 inhibits unwinding by nsp13 by affecting conformational changes during the course of the reaction or translocation on the nucleic acid. SSYA10-001 will be a valuable tool for studying the specific role of nsp13 in the SARS-CoV life cycle, which could be a model for other nidoviruses and also a candidate for further development as a SARS antiviral target.
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Sarafianos</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Biochemistry, University of Missouri</s1><s2>Columbia, Missouri</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">12-0363176</idno><date when="2012">2012</date><idno type="stanalyst">PASCAL 12-0363176 INIST</idno><idno type="RBID">Pascal:12-0363176</idno><idno type="wicri:Area/PascalFrancis/Corpus">000049</idno><idno type="wicri:Area/PascalFrancis/Curation">000938</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Severe Acute Respiratory Syndrome Coronavirus Replication Inhibitor That Interferes with the Nucleic Acid Unwinding of the Viral Helicase</title><author><name sortKey="Adedeji, Adeyemi O" sort="Adedeji, Adeyemi O" uniqKey="Adedeji A" first="Adeyemi O." last="Adedeji">Adeyemi O. Adedeji</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Singh, Kamalendra" sort="Singh, Kamalendra" uniqKey="Singh K" first="Kamalendra" last="Singh">Kamalendra Singh</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Calcaterra, Nicholas E" sort="Calcaterra, Nicholas E" uniqKey="Calcaterra N" first="Nicholas E." last="Calcaterra">Nicholas E. Calcaterra</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Biochemistry, University of Missouri</s1><s2>Columbia, Missouri</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Dediego, Marta L" sort="Dediego, Marta L" uniqKey="Dediego M" first="Marta L." last="Dediego">Marta L. Dediego</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Centro Nacional de Biotecnología-CSIC Spanish Council for Scientific Research, Campus Universidad Autónoma</s1><s2>Madrid</s2><s3>ESP</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Espagne</country></affiliation></author><author><name sortKey="Enjuanes, Luis" sort="Enjuanes, Luis" uniqKey="Enjuanes L" first="Luis" last="Enjuanes">Luis Enjuanes</name><affiliation wicri:level="1"><inist:fA14 i1="03"><s1>Centro Nacional de Biotecnología-CSIC Spanish Council for Scientific Research, Campus Universidad Autónoma</s1><s2>Madrid</s2><s3>ESP</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>Espagne</country></affiliation></author><author><name sortKey="Weiss, Susan" sort="Weiss, Susan" uniqKey="Weiss S" first="Susan" last="Weiss">Susan Weiss</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Department of Microbiology, University of Pennsylvania, School of Medicine</s1><s2>Philadelphia, Pennsylvania</s2><s3>USA</s3><sZ>6 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author><author><name sortKey="Sarafianos, Stefan G" sort="Sarafianos, Stefan G" uniqKey="Sarafianos S" first="Stefan G." last="Sarafianos">Stefan G. Sarafianos</name><affiliation wicri:level="1"><inist:fA14 i1="01"><s1>Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Department of Biochemistry, University of Missouri</s1><s2>Columbia, Missouri</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>États-Unis</country></affiliation></author></analytic><series><title level="j" type="main">Antimicrobial agents and chemotherapy</title><title level="j" type="abbreviated">Antimicrob. agents chemother.</title><idno type="ISSN">0066-4804</idno><imprint><date when="2012">2012</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Antimicrobial agents and chemotherapy</title><title level="j" type="abbreviated">Antimicrob. agents chemother.</title><idno type="ISSN">0066-4804</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Coronavirus</term><term>Inhibitor</term><term>Nucleic acid</term><term>Replication</term><term>Severe acute respiratory syndrome</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Syndrome respiratoire aigu sévère</term><term>Coronavirus</term><term>Réplication</term><term>Inhibiteur</term><term>Acide nucléique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome (SARS) is a highly contagious disease, caused by SARS coronavirus (SARS-CoV), for which there are no approved treatments. We report the discovery of a potent inhibitor of SARS-CoV that blocks replication by inhibiting the unwinding activity of the SARS-CoV helicase (nsp13). We used a Förster resonance energy transfer (FRET)-based helicase assay to screen the Maybridge Hitfinder chemical library. We identified and validated a compound (SSYA10-001) that specifically blocks the double-stranded RNA (dsRNA) and dsDNA unwinding activities of nsp13, with 50% inhibitory concentrations (IC<sub>50</sub>s) of 5.70 and 5.30 μM, respectively. This compound also has inhibitory activity (50% effective concentration [EC<sub>50</sub>] = 8.95 μM) in a SARS-CoV replicon assay, with low cytotoxicity (50% cytotoxic concentration [CC<sub>50</sub>] = >250 μM), suggesting that the helicase plays a still unidentified critical role in the SARS-CoV life cycle. Enzyme kinetic studies on the mechanism of nsp13 inhibition revealed that SSYA10-001 acts as a noncompetitive inhibitor of nsp13 with respect to nucleic acid and ATP substrates. Moreover, SSYA10-001 does not affect ATP hydrolysis or nsp13 binding to the nucleic acid substrate. SSYA10-001 did not inhibit hepatitis C virus (HCV) helicase, other bacterial and viral RNA-dependent RNA polymerases, or reverse transcriptase. These results suggest that SSYA10-001 specifically blocks nsp13 through a novel mechanism and is less likely to interfere with the functions of cellular enzymes that process nucleic acids or ATP. Hence, it is possible that SSYA10-001 inhibits unwinding by nsp13 by affecting conformational changes during the course of the reaction or translocation on the nucleic acid. SSYA10-001 will be a valuable tool for studying the specific role of nsp13 in the SARS-CoV life cycle, which could be a model for other nidoviruses and also a candidate for further development as a SARS antiviral target.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0066-4804</s0></fA01><fA02 i1="01"><s0>AACHAX</s0></fA02><fA03 i2="1"><s0>Antimicrob. agents chemother.</s0></fA03><fA05><s2>56</s2></fA05><fA06><s2>9</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Severe Acute Respiratory Syndrome Coronavirus Replication Inhibitor That Interferes with the Nucleic Acid Unwinding of the Viral Helicase</s1></fA08><fA11 i1="01" i2="1"><s1>ADEDEJI (Adeyemi O.)</s1></fA11><fA11 i1="02" i2="1"><s1>SINGH (Kamalendra)</s1></fA11><fA11 i1="03" i2="1"><s1>CALCATERRA (Nicholas E.)</s1></fA11><fA11 i1="04" i2="1"><s1>DEDIEGO (Marta L.)</s1></fA11><fA11 i1="05" i2="1"><s1>ENJUANES (Luis)</s1></fA11><fA11 i1="06" i2="1"><s1>WEISS (Susan)</s1></fA11><fA11 i1="07" i2="1"><s1>SARAFIANOS (Stefan G.)</s1></fA11><fA14 i1="01"><s1>Christopher S. Bond Life Sciences Center, Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine</s1><s3>USA</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="02"><s1>Department of Biochemistry, University of Missouri</s1><s2>Columbia, Missouri</s2><s3>USA</s3><sZ>3 aut.</sZ><sZ>7 aut.</sZ></fA14><fA14 i1="03"><s1>Centro Nacional de Biotecnología-CSIC Spanish Council for Scientific Research, Campus Universidad Autónoma</s1><s2>Madrid</s2><s3>ESP</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></fA14><fA14 i1="04"><s1>Department of Microbiology, University of Pennsylvania, School of Medicine</s1><s2>Philadelphia, Pennsylvania</s2><s3>USA</s3><sZ>6 aut.</sZ></fA14><fA20><s1>4718-4728</s1></fA20><fA21><s1>2012</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>13334</s2><s5>354000504464350210</s5></fA43><fA44><s0>0000</s0><s1>© 2012 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>73 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>12-0363176</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Antimicrobial agents and chemotherapy</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>Severe acute respiratory syndrome (SARS) is a highly contagious disease, caused by SARS coronavirus (SARS-CoV), for which there are no approved treatments. We report the discovery of a potent inhibitor of SARS-CoV that blocks replication by inhibiting the unwinding activity of the SARS-CoV helicase (nsp13). We used a Förster resonance energy transfer (FRET)-based helicase assay to screen the Maybridge Hitfinder chemical library. We identified and validated a compound (SSYA10-001) that specifically blocks the double-stranded RNA (dsRNA) and dsDNA unwinding activities of nsp13, with 50% inhibitory concentrations (IC<sub>50</sub>s) of 5.70 and 5.30 μM, respectively. This compound also has inhibitory activity (50% effective concentration [EC<sub>50</sub>] = 8.95 μM) in a SARS-CoV replicon assay, with low cytotoxicity (50% cytotoxic concentration [CC<sub>50</sub>] = >250 μM), suggesting that the helicase plays a still unidentified critical role in the SARS-CoV life cycle. Enzyme kinetic studies on the mechanism of nsp13 inhibition revealed that SSYA10-001 acts as a noncompetitive inhibitor of nsp13 with respect to nucleic acid and ATP substrates. Moreover, SSYA10-001 does not affect ATP hydrolysis or nsp13 binding to the nucleic acid substrate. SSYA10-001 did not inhibit hepatitis C virus (HCV) helicase, other bacterial and viral RNA-dependent RNA polymerases, or reverse transcriptase. These results suggest that SSYA10-001 specifically blocks nsp13 through a novel mechanism and is less likely to interfere with the functions of cellular enzymes that process nucleic acids or ATP. Hence, it is possible that SSYA10-001 inhibits unwinding by nsp13 by affecting conformational changes during the course of the reaction or translocation on the nucleic acid. SSYA10-001 will be a valuable tool for studying the specific role of nsp13 in the SARS-CoV life cycle, which could be a model for other nidoviruses and also a candidate for further development as a SARS antiviral target.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02S</s0></fC02><fC02 i1="02" i2="X"><s0>002B05C02C</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Syndrome respiratoire aigu sévère</s0><s2>NM</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Severe acute respiratory syndrome</s0><s2>NM</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Síndrome respiratorio agudo severo</s0><s2>NM</s2><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Coronavirus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Coronavirus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Coronavirus</s0><s2>NW</s2><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Réplication</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Replication</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Replicación</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Inhibiteur</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Inhibitor</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Inhibidor</s0><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Acide nucléique</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Nucleic acid</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Acido nucleico</s0><s5>05</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Virose</s0></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Viral disease</s0></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Virosis</s0></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Infection</s0></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Infection</s0></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Infección</s0></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Coronaviridae</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Nidovirales</s0><s2>NW</s2></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Virus</s0><s2>NW</s2></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Pathologie de l'appareil respiratoire</s0><s5>37</s5></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Respiratory disease</s0><s5>37</s5></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Aparato respiratorio patología</s0><s5>37</s5></fC07><fC07 i1="07" i2="X" l="FRE"><s0>Pathologie des poumons</s0><s5>38</s5></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Lung disease</s0><s5>38</s5></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Pulmón patología</s0><s5>38</s5></fC07><fN21><s1>282</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard></inist></record>Pour manipuler ce document sous Unix (Dilib)
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