Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus.
Identifieur interne : 001C76 ( PubMed/Checkpoint ); précédent : 001C75; suivant : 001C77Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus.
Auteurs : D H Goetz [États-Unis] ; Y. Choe ; E. Hansell ; Y T Chen ; M. Mcdowell ; C B Jonsson ; W R Roush ; J. Mckerrow ; C S CraikSource :
- Biochemistry [ 0006-2960 ] ; 2007.
Descripteurs français
- KwdFr :
- Animaux, Antiviraux (), Antiviraux (isolement et purification), Antiviraux (métabolisme), Antiviraux (pharmacologie), Banque de peptides, Cellules Vero, Composés époxy (), Composés époxy (isolement et purification), Composés époxy (métabolisme), Composés époxy (pharmacologie), Cristallographie aux rayons X, Cysteine endopeptidases (), Dipeptides (), Dipeptides (isolement et purification), Dipeptides (métabolisme), Dipeptides (pharmacologie), Domaine catalytique (), Inhibiteurs de la cystéine protéinase (), Inhibiteurs de la cystéine protéinase (pharmacologie), Modèles moléculaires, Oligopeptides (), Oligopeptides (isolement et purification), Oligopeptides (métabolisme), Oligopeptides (pharmacologie), Protéines virales (), Protéines virales (antagonistes et inhibiteurs), Relation structure-activité, Réplication virale (), Spécificité du substrat, Structure tertiaire des protéines, Substitution d'acide aminé, Virus du SRAS (), Virus du SRAS (enzymologie).
- MESH :
- antagonistes et inhibiteurs : Protéines virales.
- enzymologie : Virus du SRAS.
- isolement et purification : Antiviraux, Composés époxy, Dipeptides, Oligopeptides.
- métabolisme : Antiviraux, Composés époxy, Dipeptides, Oligopeptides.
- pharmacologie : Antiviraux, Composés époxy, Dipeptides, Inhibiteurs de la cystéine protéinase, Oligopeptides.
- Animaux, Antiviraux, Banque de peptides, Cellules Vero, Composés époxy, Cristallographie aux rayons X, Cysteine endopeptidases, Dipeptides, Domaine catalytique, Inhibiteurs de la cystéine protéinase, Modèles moléculaires, Oligopeptides, Protéines virales, Relation structure-activité, Réplication virale, Spécificité du substrat, Structure tertiaire des protéines, Substitution d'acide aminé, Virus du SRAS.
English descriptors
- KwdEn :
- Amino Acid Substitution, Animals, Antiviral Agents (chemistry), Antiviral Agents (isolation & purification), Antiviral Agents (metabolism), Antiviral Agents (pharmacology), Catalytic Domain (drug effects), Chlorocebus aethiops, Crystallography, X-Ray, Cysteine Endopeptidases (chemistry), Cysteine Proteinase Inhibitors (chemistry), Cysteine Proteinase Inhibitors (classification), Cysteine Proteinase Inhibitors (pharmacology), Dipeptides (chemistry), Dipeptides (isolation & purification), Dipeptides (metabolism), Dipeptides (pharmacology), Epoxy Compounds (chemistry), Epoxy Compounds (isolation & purification), Epoxy Compounds (metabolism), Epoxy Compounds (pharmacology), Models, Molecular, Oligopeptides (chemistry), Oligopeptides (isolation & purification), Oligopeptides (metabolism), Oligopeptides (pharmacology), Peptide Library, Protein Structure, Tertiary, SARS Virus (drug effects), SARS Virus (enzymology), Structure-Activity Relationship, Substrate Specificity, Vero Cells, Viral Proteins (antagonists & inhibitors), Viral Proteins (chemistry), Virus Replication (drug effects).
- MESH :
- chemical , antagonists & inhibitors : Viral Proteins.
- chemical , chemistry : Antiviral Agents, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Dipeptides, Epoxy Compounds, Oligopeptides, Viral Proteins.
- chemical , classification : Cysteine Proteinase Inhibitors.
- chemical , isolation & purification : Antiviral Agents, Dipeptides, Epoxy Compounds, Oligopeptides.
- chemical , metabolism : Antiviral Agents, Dipeptides, Epoxy Compounds, Oligopeptides.
- chemical , pharmacology : Antiviral Agents, Cysteine Proteinase Inhibitors, Dipeptides, Epoxy Compounds, Oligopeptides.
- drug effects : Catalytic Domain, SARS Virus, Virus Replication.
- enzymology : SARS Virus.
- Amino Acid Substitution, Animals, Chlorocebus aethiops, Crystallography, X-Ray, Models, Molecular, Peptide Library, Protein Structure, Tertiary, Structure-Activity Relationship, Substrate Specificity, Vero Cells.
Abstract
Severe acute respiratory syndrome (SARS) is an emerging infectious disease associated with a high rate of mortality. The SARS-associated coronavirus (SARS-CoV) has been identified as the etiological agent of the disease. Although public health procedures have been effective in combating the spread of SARS, concern remains about the possibility of a recurrence. Various approaches are being pursued for the development of efficacious therapeutics. One promising approach is to develop small molecule inhibitors of the essential major polyprotein processing protease 3Clpro. Here we report a complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160,000 possible naturally occurring tetrapeptides. The substrate specificity data show the expected P1-Gln P2-Leu specificity and elucidate a novel preference for P1-His containing substrates equal to the expected preference for P1-Gln. These data were then used to develop optimal substrates for a high-throughput screen of a 2000 compound small-molecule inhibitor library consisting of known cysteine protease inhibitor scaffolds. We also report the 1.8 A X-ray crystal structure of 3Clpro bound to an irreversible inhibitor. This inhibitor, an alpha,beta-epoxyketone, inhibits 3Clpro with a k3/Ki of 0.002 microM(-1) s(-1) in a mode consistent with the substrate specificity data. Finally, we report the successful rational improvement of this scaffold with second generation inhibitors. These data provide the foundation for a rational small-molecule inhibitor design effort based upon the inhibitor scaffold identified, the crystal structure of the complex, and a more complete understanding of P1-P4 substrate specificity.
DOI: 10.1021/bi0621415
PubMed: 17605471
Affiliations:
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pubmed:17605471Le document en format XML
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xml:lang="fr"><term>Animaux</term><term>Antiviraux</term><term>Banque de peptides</term><term>Cellules Vero</term><term>Composés époxy</term><term>Cristallographie aux rayons X</term><term>Cysteine endopeptidases</term><term>Dipeptides</term><term>Domaine catalytique</term><term>Inhibiteurs de la cystéine protéinase</term><term>Modèles moléculaires</term><term>Oligopeptides</term><term>Protéines virales</term><term>Relation structure-activité</term><term>Réplication virale</term><term>Spécificité du substrat</term><term>Structure tertiaire des protéines</term><term>Substitution d'acide aminé</term><term>Virus du SRAS</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Severe acute respiratory syndrome (SARS) is an emerging infectious disease associated with a high rate of mortality. The SARS-associated coronavirus (SARS-CoV) has been identified as the etiological agent of the disease. Although public health procedures have been effective in combating the spread of SARS, concern remains about the possibility of a recurrence. Various approaches are being pursued for the development of efficacious therapeutics. One promising approach is to develop small molecule inhibitors of the essential major polyprotein processing protease 3Clpro. Here we report a complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160,000 possible naturally occurring tetrapeptides. The substrate specificity data show the expected P1-Gln P2-Leu specificity and elucidate a novel preference for P1-His containing substrates equal to the expected preference for P1-Gln. These data were then used to develop optimal substrates for a high-throughput screen of a 2000 compound small-molecule inhibitor library consisting of known cysteine protease inhibitor scaffolds. We also report the 1.8 A X-ray crystal structure of 3Clpro bound to an irreversible inhibitor. This inhibitor, an alpha,beta-epoxyketone, inhibits 3Clpro with a k3/Ki of 0.002 microM(-1) s(-1) in a mode consistent with the substrate specificity data. Finally, we report the successful rational improvement of this scaffold with second generation inhibitors. These data provide the foundation for a rational small-molecule inhibitor design effort based upon the inhibitor scaffold identified, the crystal structure of the complex, and a more complete understanding of P1-P4 substrate specificity.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">17605471</PMID><DateCompleted><Year>2007</Year><Month>09</Month><Day>19</Day></DateCompleted><DateRevised><Year>2020</Year><Month>03</Month><Day>25</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Print">0006-2960</ISSN><JournalIssue CitedMedium="Print"><Volume>46</Volume><Issue>30</Issue><PubDate><Year>2007</Year><Month>Jul</Month><Day>31</Day></PubDate></JournalIssue><Title>Biochemistry</Title><ISOAbbreviation>Biochemistry</ISOAbbreviation></Journal><ArticleTitle>Substrate specificity profiling and identification of a new class of inhibitor for the major protease of the SARS coronavirus.</ArticleTitle><Pagination><MedlinePgn>8744-52</MedlinePgn></Pagination><Abstract><AbstractText>Severe acute respiratory syndrome (SARS) is an emerging infectious disease associated with a high rate of mortality. The SARS-associated coronavirus (SARS-CoV) has been identified as the etiological agent of the disease. Although public health procedures have been effective in combating the spread of SARS, concern remains about the possibility of a recurrence. Various approaches are being pursued for the development of efficacious therapeutics. One promising approach is to develop small molecule inhibitors of the essential major polyprotein processing protease 3Clpro. Here we report a complete description of the tetrapeptide substrate specificity of 3Clpro using fully degenerate peptide libraries consisting of all 160,000 possible naturally occurring tetrapeptides. The substrate specificity data show the expected P1-Gln P2-Leu specificity and elucidate a novel preference for P1-His containing substrates equal to the expected preference for P1-Gln. These data were then used to develop optimal substrates for a high-throughput screen of a 2000 compound small-molecule inhibitor library consisting of known cysteine protease inhibitor scaffolds. We also report the 1.8 A X-ray crystal structure of 3Clpro bound to an irreversible inhibitor. This inhibitor, an alpha,beta-epoxyketone, inhibits 3Clpro with a k3/Ki of 0.002 microM(-1) s(-1) in a mode consistent with the substrate specificity data. Finally, we report the successful rational improvement of this scaffold with second generation inhibitors. These data provide the foundation for a rational small-molecule inhibitor design effort based upon the inhibitor scaffold identified, the crystal structure of the complex, and a more complete understanding of P1-P4 substrate specificity.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Goetz</LastName><ForeName>D H</ForeName><Initials>DH</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Choe</LastName><ForeName>Y</ForeName><Initials>Y</Initials></Author><Author ValidYN="Y"><LastName>Hansell</LastName><ForeName>E</ForeName><Initials>E</Initials></Author><Author ValidYN="Y"><LastName>Chen</LastName><ForeName>Y T</ForeName><Initials>YT</Initials></Author><Author ValidYN="Y"><LastName>McDowell</LastName><ForeName>M</ForeName><Initials>M</Initials></Author><Author ValidYN="Y"><LastName>Jonsson</LastName><ForeName>C B</ForeName><Initials>CB</Initials></Author><Author ValidYN="Y"><LastName>Roush</LastName><ForeName>W R</ForeName><Initials>WR</Initials></Author><Author ValidYN="Y"><LastName>McKerrow</LastName><ForeName>J</ForeName><Initials>J</Initials></Author><Author ValidYN="Y"><LastName>Craik</LastName><ForeName>C S</ForeName><Initials>CS</Initials></Author></AuthorList><Language>eng</Language><DataBankList CompleteYN="Y"><DataBank><DataBankName>PDB</DataBankName><AccessionNumberList><AccessionNumber>2OP9</AccessionNumber></AccessionNumberList></DataBank></DataBankList><GrantList CompleteYN="Y"><Grant><GrantID>AI035707</GrantID><Acronym>AI</Acronym><Agency>NIAID NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>GM069243</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant><Grant><GrantID>GM56531</GrantID><Acronym>GM</Acronym><Agency>NIGMS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2007</Year><Month>07</Month><Day>03</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Biochemistry</MedlineTA><NlmUniqueID>0370623</NlmUniqueID><ISSNLinking>0006-2960</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000998">Antiviral Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D015853">Cysteine Proteinase Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004151">Dipeptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004852">Epoxy Compounds</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009842">Oligopeptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D019151">Peptide Library</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014764">Viral Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C522763">WRR 182</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C522764">WRR 183</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C522765">WRR 495</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="D019943" MajorTopicYN="N">Amino Acid Substitution</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000998" MajorTopicYN="N">Antiviral Agents</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000302" MajorTopicYN="Y">isolation & purification</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020134" MajorTopicYN="N">Catalytic Domain</DescriptorName><QualifierName UI="Q000187" MajorTopicYN="N">drug effects</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D002522" MajorTopicYN="N">Chlorocebus aethiops</DescriptorName></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></MeshHeading><MeshHeading><DescriptorName UI="D015853" MajorTopicYN="N">Cysteine Proteinase Inhibitors</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000145" MajorTopicYN="N">classification</QualifierName><QualifierName UI="Q000494" MajorTopicYN="Y">pharmacology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004151" MajorTopicYN="N">Dipeptides</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000302" MajorTopicYN="N">isolation & 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IdType="doi">10.1021/bi0621415</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>États-Unis</li></country></list><tree><noCountry><name sortKey="Chen, Y T" sort="Chen, Y T" uniqKey="Chen Y" first="Y T" last="Chen">Y T Chen</name><name sortKey="Choe, Y" sort="Choe, Y" uniqKey="Choe Y" first="Y" last="Choe">Y. Choe</name><name sortKey="Craik, C S" sort="Craik, C S" uniqKey="Craik C" first="C S" last="Craik">C S Craik</name><name sortKey="Hansell, E" sort="Hansell, E" uniqKey="Hansell E" first="E" last="Hansell">E. Hansell</name><name sortKey="Jonsson, C B" sort="Jonsson, C B" uniqKey="Jonsson C" first="C B" last="Jonsson">C B Jonsson</name><name sortKey="Mcdowell, M" sort="Mcdowell, M" uniqKey="Mcdowell M" first="M" last="Mcdowell">M. Mcdowell</name><name sortKey="Mckerrow, J" sort="Mckerrow, J" uniqKey="Mckerrow J" first="J" last="Mckerrow">J. Mckerrow</name><name sortKey="Roush, W R" sort="Roush, W R" uniqKey="Roush W" first="W R" last="Roush">W R Roush</name></noCountry><country name="États-Unis"><noRegion><name sortKey="Goetz, D H" sort="Goetz, D H" uniqKey="Goetz D" first="D H" last="Goetz">D H Goetz</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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