Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease.
Identifieur interne : 001479 ( PubMed/Curation ); précédent : 001478; suivant : 001480Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease.
Auteurs : Lili Zhu [Allemagne] ; Shyla George ; Marco F. Schmidt ; Samer I. Al-Gharabli ; Jörg Rademann ; Rolf HilgenfeldSource :
- Antiviral research [ 1872-9096 ] ; 2011.
Descripteurs français
- KwdFr :
- Aldéhydes (pharmacologie), Antienzymes (pharmacologie), Cinétique, Conformation des protéines, Cristallographie aux rayons X, Cysteine endopeptidases (), Cysteine endopeptidases (métabolisme), Modèles moléculaires, Peptides (métabolisme), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Protéines virales (métabolisme), Spécificité du substrat (), Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- métabolisme : Cysteine endopeptidases, Peptides, Protéines virales.
- pharmacologie : Aldéhydes, Antienzymes.
- Cinétique, Conformation des protéines, Cristallographie aux rayons X, Cysteine endopeptidases, Modèles moléculaires, Protéines virales, Spécificité du substrat, Virus du SRAS.
English descriptors
- KwdEn :
- Aldehydes (pharmacology), Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Endopeptidases (metabolism), Enzyme Inhibitors (pharmacology), Kinetics, Models, Molecular, Peptides (metabolism), Protein Conformation, SARS Virus (drug effects), SARS Virus (enzymology), Substrate Specificity (drug effects), Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Viral Proteins (metabolism).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Cysteine Endopeptidases, Viral Proteins.
- chemical , metabolism : Cysteine Endopeptidases, Peptides, Viral Proteins.
- chemical , pharmacology : Aldehydes, Enzyme Inhibitors.
- drug effects : SARS Virus, Substrate Specificity.
- enzymology : SARS Virus.
- Crystallography, X-Ray, Kinetics, Models, Molecular, Protein Conformation.
Abstract
SARS coronavirus main protease (SARS-CoV M(pro)) is essential for the replication of the virus and regarded as a major antiviral drug target. The enzyme is a cysteine protease, with a catalytic dyad (Cys-145/His-41) in the active site. Aldehyde inhibitors can bind reversibly to the active-site sulfhydryl of SARS-CoV M(pro). Previous studies using peptidic substrates and inhibitors showed that the substrate specificity of SARS-CoV M(pro) requires glutamine in the P1 position and a large hydrophobic residue in the P2 position. We determined four crystal structures of SARS-CoV M(pro) in complex with pentapeptide aldehydes (Ac-ESTLQ-H, Ac-NSFSQ-H, Ac-DSFDQ-H, and Ac-NSTSQ-H). Kinetic data showed that all of these aldehydes exhibit inhibitory activity towards SARS-CoV M(pro), with K(i) values in the μM range. Surprisingly, the X-ray structures revealed that the hydrophobic S2 pocket of the enzyme can accommodate serine and even aspartic-acid side-chains in the P2 positions of the inhibitors. Consequently, we reassessed the substrate specificity of the enzyme by testing the cleavage of 20 different tetradecapeptide substrates with varying amino-acid residues in the P2 position. The cleavage efficiency for the substrate with serine in the P2 position was 160-times lower than that for the original substrate (P2=Leu); furthermore, the substrate with aspartic acid in the P2 position was not cleaved at all. We also determined a crystal structure of SARS-CoV M(pro) in complex with aldehyde Cm-FF-H, which has its P1-phenylalanine residue bound to the relatively hydrophilic S1 pocket of the enzyme and yet exhibits a high inhibitory activity against SARS-CoV M(pro), with K(i)=2.24±0.58 μM. These results show that the stringent substrate specificity of the SARS-CoV M(pro) with respect to the P1 and P2 positions can be overruled by the highly electrophilic character of the aldehyde warhead, thereby constituting a deviation from the dogma that peptidic inhibitors need to correspond to the observed cleavage specificity of the target protease.
DOI: 10.1016/j.antiviral.2011.08.001
PubMed: 21854807
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Al-Gharabli</name></author><author><name sortKey="Rademann, Jorg" sort="Rademann, Jorg" uniqKey="Rademann J" first="Jörg" last="Rademann">Jörg Rademann</name></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name></author></analytic><series><title level="j">Antiviral research</title><idno type="eISSN">1872-9096</idno><imprint><date when="2011" type="published">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Aldehydes (pharmacology)</term><term>Crystallography, X-Ray</term><term>Cysteine Endopeptidases (chemistry)</term><term>Cysteine Endopeptidases (metabolism)</term><term>Enzyme Inhibitors (pharmacology)</term><term>Kinetics</term><term>Models, Molecular</term><term>Peptides (metabolism)</term><term>Protein Conformation</term><term>SARS Virus (drug effects)</term><term>SARS Virus (enzymology)</term><term>Substrate Specificity (drug effects)</term><term>Viral Proteins (antagonists & inhibitors)</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Aldéhydes (pharmacologie)</term><term>Antienzymes (pharmacologie)</term><term>Cinétique</term><term>Conformation des protéines</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases ()</term><term>Cysteine endopeptidases (métabolisme)</term><term>Modèles moléculaires</term><term>Peptides (métabolisme)</term><term>Protéines virales ()</term><term>Protéines virales (antagonistes et inhibiteurs)</term><term>Protéines virales (métabolisme)</term><term>Spécificité du substrat ()</term><term>Virus du SRAS ()</term><term>Virus du SRAS (enzymologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cysteine Endopeptidases</term><term>Peptides</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Aldehydes</term><term>Enzyme Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>SARS Virus</term><term>Substrate Specificity</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Cysteine endopeptidases</term><term>Peptides</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Aldéhydes</term><term>Antienzymes</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Crystallography, X-Ray</term><term>Kinetics</term><term>Models, Molecular</term><term>Protein Conformation</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Cinétique</term><term>Conformation des protéines</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases</term><term>Modèles moléculaires</term><term>Protéines virales</term><term>Spécificité du substrat</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">SARS coronavirus main protease (SARS-CoV M(pro)) is essential for the replication of the virus and regarded as a major antiviral drug target. The enzyme is a cysteine protease, with a catalytic dyad (Cys-145/His-41) in the active site. Aldehyde inhibitors can bind reversibly to the active-site sulfhydryl of SARS-CoV M(pro). Previous studies using peptidic substrates and inhibitors showed that the substrate specificity of SARS-CoV M(pro) requires glutamine in the P1 position and a large hydrophobic residue in the P2 position. We determined four crystal structures of SARS-CoV M(pro) in complex with pentapeptide aldehydes (Ac-ESTLQ-H, Ac-NSFSQ-H, Ac-DSFDQ-H, and Ac-NSTSQ-H). Kinetic data showed that all of these aldehydes exhibit inhibitory activity towards SARS-CoV M(pro), with K(i) values in the μM range. Surprisingly, the X-ray structures revealed that the hydrophobic S2 pocket of the enzyme can accommodate serine and even aspartic-acid side-chains in the P2 positions of the inhibitors. Consequently, we reassessed the substrate specificity of the enzyme by testing the cleavage of 20 different tetradecapeptide substrates with varying amino-acid residues in the P2 position. The cleavage efficiency for the substrate with serine in the P2 position was 160-times lower than that for the original substrate (P2=Leu); furthermore, the substrate with aspartic acid in the P2 position was not cleaved at all. We also determined a crystal structure of SARS-CoV M(pro) in complex with aldehyde Cm-FF-H, which has its P1-phenylalanine residue bound to the relatively hydrophilic S1 pocket of the enzyme and yet exhibits a high inhibitory activity against SARS-CoV M(pro), with K(i)=2.24±0.58 μM. These results show that the stringent substrate specificity of the SARS-CoV M(pro) with respect to the P1 and P2 positions can be overruled by the highly electrophilic character of the aldehyde warhead, thereby constituting a deviation from the dogma that peptidic inhibitors need to correspond to the observed cleavage specificity of the target protease.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">21854807</PMID><DateCompleted><Year>2012</Year><Month>02</Month><Day>08</Day></DateCompleted><DateRevised><Year>2020</Year><Month>04</Month><Day>07</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1872-9096</ISSN><JournalIssue CitedMedium="Internet"><Volume>92</Volume><Issue>2</Issue><PubDate><Year>2011</Year><Month>Nov</Month></PubDate></JournalIssue><Title>Antiviral research</Title><ISOAbbreviation>Antiviral Res.</ISOAbbreviation></Journal><ArticleTitle>Peptide aldehyde inhibitors challenge the substrate specificity of the SARS-coronavirus main protease.</ArticleTitle><Pagination><MedlinePgn>204-12</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1016/j.antiviral.2011.08.001</ELocationID><Abstract><AbstractText>SARS coronavirus main protease (SARS-CoV M(pro)) is essential for the replication of the virus and regarded as a major antiviral drug target. The enzyme is a cysteine protease, with a catalytic dyad (Cys-145/His-41) in the active site. Aldehyde inhibitors can bind reversibly to the active-site sulfhydryl of SARS-CoV M(pro). Previous studies using peptidic substrates and inhibitors showed that the substrate specificity of SARS-CoV M(pro) requires glutamine in the P1 position and a large hydrophobic residue in the P2 position. We determined four crystal structures of SARS-CoV M(pro) in complex with pentapeptide aldehydes (Ac-ESTLQ-H, Ac-NSFSQ-H, Ac-DSFDQ-H, and Ac-NSTSQ-H). Kinetic data showed that all of these aldehydes exhibit inhibitory activity towards SARS-CoV M(pro), with K(i) values in the μM range. Surprisingly, the X-ray structures revealed that the hydrophobic S2 pocket of the enzyme can accommodate serine and even aspartic-acid side-chains in the P2 positions of the inhibitors. Consequently, we reassessed the substrate specificity of the enzyme by testing the cleavage of 20 different tetradecapeptide substrates with varying amino-acid residues in the P2 position. The cleavage efficiency for the substrate with serine in the P2 position was 160-times lower than that for the original substrate (P2=Leu); furthermore, the substrate with aspartic acid in the P2 position was not cleaved at all. We also determined a crystal structure of SARS-CoV M(pro) in complex with aldehyde Cm-FF-H, which has its P1-phenylalanine residue bound to the relatively hydrophilic S1 pocket of the enzyme and yet exhibits a high inhibitory activity against SARS-CoV M(pro), with K(i)=2.24±0.58 μM. These results show that the stringent substrate specificity of the SARS-CoV M(pro) with respect to the P1 and P2 positions can be overruled by the highly electrophilic character of the aldehyde warhead, thereby constituting a deviation from the dogma that peptidic inhibitors need to correspond to the observed cleavage specificity of the target protease.</AbstractText><CopyrightInformation>Copyright © 2011 Elsevier B.V. All rights reserved.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Zhu</LastName><ForeName>Lili</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>George</LastName><ForeName>Shyla</ForeName><Initials>S</Initials></Author><Author ValidYN="Y"><LastName>Schmidt</LastName><ForeName>Marco F</ForeName><Initials>MF</Initials></Author><Author ValidYN="Y"><LastName>Al-Gharabli</LastName><ForeName>Samer I</ForeName><Initials>SI</Initials></Author><Author ValidYN="Y"><LastName>Rademann</LastName><ForeName>Jörg</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Hilgenfeld</LastName><ForeName>Rolf</ForeName><Initials>R</Initials></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2011</Year><Month>08</Month><Day>11</Day></ArticleDate></Article><MedlineJournalInfo><Country>Netherlands</Country><MedlineTA>Antiviral Res</MedlineTA><NlmUniqueID>8109699</NlmUniqueID><ISSNLinking>0166-3542</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000447">Aldehydes</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004791">Enzyme Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010455">Peptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014764">Viral Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.-</RegistryNumber><NameOfSubstance UI="C099456">3C-like proteinase, Coronavirus</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.22.-</RegistryNumber><NameOfSubstance UI="D003546">Cysteine Endopeptidases</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000447" MajorTopicYN="N">Aldehydes</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D018360" MajorTopicYN="N">Crystallography, X-Ray</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003546" MajorTopicYN="N">Cysteine Endopeptidases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004791" MajorTopicYN="N">Enzyme Inhibitors</DescriptorName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D007700" MajorTopicYN="N">Kinetics</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008958" MajorTopicYN="N">Models, Molecular</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010455" MajorTopicYN="N">Peptides</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D011487" MajorTopicYN="N">Protein Conformation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="Y">drug effects</QualifierName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D013379" MajorTopicYN="N">Substrate Specificity</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName 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HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Curation/RBID.i -Sk "pubmed:21854807" \
| HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Curation/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |