Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design.
Identifieur interne : 003002 ( Main/Exploration ); précédent : 003001; suivant : 003003Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design.
Auteurs : Xiaoyu Xue [République populaire de Chine] ; Hongwei Yu ; Haitao Yang ; Fei Xue ; Zhixin Wu ; Wei Shen ; Jun Li ; Zhe Zhou ; Yi Ding ; Qi Zhao ; Xuejun C. Zhang ; Ming Liao ; Mark Bartlam ; Zihe RaoSource :
- Journal of virology [ 1098-5514 ] ; 2008.
Descripteurs français
- KwdFr :
- Amorces ADN, Antiviraux (), Antiviraux (pharmacologie), Conception de médicament, Conformation des protéines, Coronavirus (), Coronavirus (enzymologie), Cristallisation, Données de séquences moléculaires, Peptide hydrolases (), Peptide hydrolases (métabolisme), Similitude de séquences d'acides aminés, Spécificité du substrat, Séquence d'acides aminés, Séquence nucléotidique.
- MESH :
- enzymologie : Coronavirus.
- métabolisme : Peptide hydrolases.
- pharmacologie : Antiviraux.
- Amorces ADN, Antiviraux, Conception de médicament, Conformation des protéines, Coronavirus, Cristallisation, Données de séquences moléculaires, Peptide hydrolases, Similitude de séquences d'acides aminés, Spécificité du substrat, Séquence d'acides aminés, Séquence nucléotidique.
English descriptors
- KwdEn :
- Amino Acid Sequence, Antiviral Agents (chemistry), Antiviral Agents (pharmacology), Base Sequence, Coronavirus (drug effects), Coronavirus (enzymology), Crystallization, DNA Primers, Drug Design, Molecular Sequence Data, Peptide Hydrolases (chemistry), Peptide Hydrolases (metabolism), Protein Conformation, Sequence Homology, Amino Acid, Substrate Specificity.
- MESH :
- chemical , chemistry : Antiviral Agents, Peptide Hydrolases.
- chemical , metabolism : Peptide Hydrolases.
- chemical , pharmacology : Antiviral Agents.
- drug effects : Coronavirus.
- enzymology : Coronavirus.
- Amino Acid Sequence, Base Sequence, Crystallization, DNA Primers, Drug Design, Molecular Sequence Data, Protein Conformation, Sequence Homology, Amino Acid, Substrate Specificity.
Abstract
Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M(pro)), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) M(pro) and a severe acute respiratory syndrome CoV (SARS-CoV) M(pro) mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M(pro). A monomeric form of IBV M(pro) was identified for the first time in CoV M(pro) structures. A comparison of these two structures to other available M(pro) structures provides new insights for the design of substrate-based inhibitors targeting CoV M(pro)s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M(pro) and was found to demonstrate in vitro inactivation of IBV M(pro) and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M(pro).
DOI: 10.1128/JVI.02114-07
PubMed: 18094151
Affiliations:
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Zhang</name></author><author><name sortKey="Liao, Ming" sort="Liao, Ming" uniqKey="Liao M" first="Ming" last="Liao">Ming Liao</name></author><author><name sortKey="Bartlam, Mark" sort="Bartlam, Mark" uniqKey="Bartlam M" first="Mark" last="Bartlam">Mark Bartlam</name></author><author><name sortKey="Rao, Zihe" sort="Rao, Zihe" uniqKey="Rao Z" first="Zihe" last="Rao">Zihe Rao</name></author></analytic><series><title level="j">Journal of virology</title><idno type="eISSN">1098-5514</idno><imprint><date when="2008" type="published">2008</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Amino Acid Sequence</term><term>Antiviral Agents (chemistry)</term><term>Antiviral Agents (pharmacology)</term><term>Base Sequence</term><term>Coronavirus (drug effects)</term><term>Coronavirus (enzymology)</term><term>Crystallization</term><term>DNA Primers</term><term>Drug Design</term><term>Molecular Sequence Data</term><term>Peptide Hydrolases (chemistry)</term><term>Peptide Hydrolases (metabolism)</term><term>Protein Conformation</term><term>Sequence Homology, Amino Acid</term><term>Substrate Specificity</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Amorces ADN</term><term>Antiviraux ()</term><term>Antiviraux (pharmacologie)</term><term>Conception de médicament</term><term>Conformation des protéines</term><term>Coronavirus ()</term><term>Coronavirus (enzymologie)</term><term>Cristallisation</term><term>Données de séquences moléculaires</term><term>Peptide hydrolases ()</term><term>Peptide hydrolases (métabolisme)</term><term>Similitude de séquences d'acides aminés</term><term>Spécificité du substrat</term><term>Séquence d'acides aminés</term><term>Séquence nucléotidique</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Antiviral Agents</term><term>Peptide Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Peptide Hydrolases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Peptide hydrolases</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Amino Acid Sequence</term><term>Base Sequence</term><term>Crystallization</term><term>DNA Primers</term><term>Drug Design</term><term>Molecular Sequence Data</term><term>Protein Conformation</term><term>Sequence Homology, Amino Acid</term><term>Substrate Specificity</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Amorces ADN</term><term>Antiviraux</term><term>Conception de médicament</term><term>Conformation des protéines</term><term>Coronavirus</term><term>Cristallisation</term><term>Données de séquences moléculaires</term><term>Peptide hydrolases</term><term>Similitude de séquences d'acides aminés</term><term>Spécificité du substrat</term><term>Séquence d'acides aminés</term><term>Séquence nucléotidique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Coronaviruses (CoVs) can infect humans and multiple species of animals, causing a wide spectrum of diseases. The coronavirus main protease (M(pro)), which plays a pivotal role in viral gene expression and replication through the proteolytic processing of replicase polyproteins, is an attractive target for anti-CoV drug design. In this study, the crystal structures of infectious bronchitis virus (IBV) M(pro) and a severe acute respiratory syndrome CoV (SARS-CoV) M(pro) mutant (H41A), in complex with an N-terminal autocleavage substrate, were individually determined to elucidate the structural flexibility and substrate binding of M(pro). A monomeric form of IBV M(pro) was identified for the first time in CoV M(pro) structures. A comparison of these two structures to other available M(pro) structures provides new insights for the design of substrate-based inhibitors targeting CoV M(pro)s. Furthermore, a Michael acceptor inhibitor (named N3) was cocrystallized with IBV M(pro) and was found to demonstrate in vitro inactivation of IBV M(pro) and potent antiviral activity against IBV in chicken embryos. This provides a feasible animal model for designing wide-spectrum inhibitors against CoV-associated diseases. The structure-based optimization of N3 has yielded two more efficacious lead compounds, N27 and H16, with potent inhibition against SARS-CoV M(pro).</div></front></TEI><affiliations><list><country><li>République populaire de Chine</li></country><settlement><li>Pékin</li></settlement></list><tree><noCountry><name sortKey="Bartlam, Mark" sort="Bartlam, Mark" uniqKey="Bartlam M" first="Mark" last="Bartlam">Mark Bartlam</name><name sortKey="Ding, Yi" sort="Ding, Yi" uniqKey="Ding Y" first="Yi" last="Ding">Yi Ding</name><name sortKey="Li, Jun" sort="Li, Jun" uniqKey="Li J" first="Jun" last="Li">Jun Li</name><name sortKey="Liao, Ming" sort="Liao, Ming" uniqKey="Liao M" first="Ming" last="Liao">Ming Liao</name><name sortKey="Rao, Zihe" sort="Rao, Zihe" uniqKey="Rao Z" first="Zihe" last="Rao">Zihe Rao</name><name sortKey="Shen, Wei" sort="Shen, Wei" uniqKey="Shen W" first="Wei" last="Shen">Wei Shen</name><name sortKey="Wu, Zhixin" sort="Wu, Zhixin" uniqKey="Wu Z" first="Zhixin" last="Wu">Zhixin Wu</name><name sortKey="Xue, Fei" sort="Xue, Fei" uniqKey="Xue F" first="Fei" last="Xue">Fei Xue</name><name sortKey="Yang, Haitao" sort="Yang, Haitao" uniqKey="Yang H" first="Haitao" last="Yang">Haitao Yang</name><name sortKey="Yu, Hongwei" sort="Yu, Hongwei" uniqKey="Yu H" first="Hongwei" last="Yu">Hongwei Yu</name><name sortKey="Zhang, Xuejun C" sort="Zhang, Xuejun C" uniqKey="Zhang X" first="Xuejun C" last="Zhang">Xuejun C. Zhang</name><name sortKey="Zhao, Qi" sort="Zhao, Qi" uniqKey="Zhao Q" first="Qi" last="Zhao">Qi Zhao</name><name sortKey="Zhou, Zhe" sort="Zhou, Zhe" uniqKey="Zhou Z" first="Zhe" last="Zhou">Zhe Zhou</name></noCountry><country name="République populaire de Chine"><noRegion><name sortKey="Xue, Xiaoyu" sort="Xue, Xiaoyu" uniqKey="Xue X" first="Xiaoyu" last="Xue">Xiaoyu Xue</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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