Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.
Identifieur interne : 000186 ( PubMed/Corpus ); précédent : 000185; suivant : 000187Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.
Auteurs : Linlin Zhang ; Daizong Lin ; Xinyuanyuan Sun ; Ute Curth ; Christian Drosten ; Lucie Sauerhering ; Stephan Becker ; Katharina Rox ; Rolf HilgenfeldSource :
- Science (New York, N.Y.) [ 1095-9203 ] ; 2020.
Abstract
The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, 3CLpro), due to its essential role in processing the polyproteins that are translated from the viral RNA. We report the X-ray structures of the unliganded SARS-CoV-2 Mpro and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. Based on the structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 Mpro The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.
DOI: 10.1126/science.abb3405
PubMed: 32198291
Links to Exploration step
pubmed:32198291Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.</title><author><name sortKey="Zhang, Linlin" sort="Zhang, Linlin" uniqKey="Zhang L" first="Linlin" last="Zhang">Linlin Zhang</name><affiliation><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Lin, Daizong" sort="Lin, Daizong" uniqKey="Lin D" first="Daizong" last="Lin">Daizong Lin</name><affiliation><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Sun, Xinyuanyuan" sort="Sun, Xinyuanyuan" uniqKey="Sun X" first="Xinyuanyuan" last="Sun">Xinyuanyuan Sun</name><affiliation><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Curth, Ute" sort="Curth, Ute" uniqKey="Curth U" first="Ute" last="Curth">Ute Curth</name><affiliation><nlm:affiliation>Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation><nlm:affiliation>Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Sauerhering, Lucie" sort="Sauerhering, Lucie" uniqKey="Sauerhering L" first="Lucie" last="Sauerhering">Lucie Sauerhering</name><affiliation><nlm:affiliation>Institute of Virology, University of Marburg, 35043 Marburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Becker, Stephan" sort="Becker, Stephan" uniqKey="Becker S" first="Stephan" last="Becker">Stephan Becker</name><affiliation><nlm:affiliation>Institute of Virology, University of Marburg, 35043 Marburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Rox, Katharina" sort="Rox, Katharina" uniqKey="Rox K" first="Katharina" last="Rox">Katharina Rox</name><affiliation><nlm:affiliation>Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><affiliation><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany. rolf.hilgenfeld@uni-luebeck.de.</nlm:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2020">2020</date><idno type="RBID">pubmed:32198291</idno><idno type="pmid">32198291</idno><idno type="doi">10.1126/science.abb3405</idno><idno type="wicri:Area/PubMed/Corpus">000186</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000186</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.</title><author><name sortKey="Zhang, Linlin" sort="Zhang, Linlin" uniqKey="Zhang L" first="Linlin" last="Zhang">Linlin Zhang</name><affiliation><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Lin, Daizong" sort="Lin, Daizong" uniqKey="Lin D" first="Daizong" last="Lin">Daizong Lin</name><affiliation><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Sun, Xinyuanyuan" sort="Sun, Xinyuanyuan" uniqKey="Sun X" first="Xinyuanyuan" last="Sun">Xinyuanyuan Sun</name><affiliation><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Curth, Ute" sort="Curth, Ute" uniqKey="Curth U" first="Ute" last="Curth">Ute Curth</name><affiliation><nlm:affiliation>Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><affiliation><nlm:affiliation>Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Sauerhering, Lucie" sort="Sauerhering, Lucie" uniqKey="Sauerhering L" first="Lucie" last="Sauerhering">Lucie Sauerhering</name><affiliation><nlm:affiliation>Institute of Virology, University of Marburg, 35043 Marburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Becker, Stephan" sort="Becker, Stephan" uniqKey="Becker S" first="Stephan" last="Becker">Stephan Becker</name><affiliation><nlm:affiliation>Institute of Virology, University of Marburg, 35043 Marburg, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Rox, Katharina" sort="Rox, Katharina" uniqKey="Rox K" first="Katharina" last="Rox">Katharina Rox</name><affiliation><nlm:affiliation>Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.</nlm:affiliation></affiliation></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><affiliation><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany. rolf.hilgenfeld@uni-luebeck.de.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Science (New York, N.Y.)</title><idno type="eISSN">1095-9203</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. An attractive drug target among coronaviruses is the main protease (M<sup>pro</sup>, 3CL<sup>pro</sup>), due to its essential role in processing the polyproteins that are translated from the viral RNA. We report the X-ray structures of the unliganded SARS-CoV-2 M<sup>pro</sup> and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. Based on the structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M<sup>pro</sup> The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.</div></front></TEI><pubmed><MedlineCitation Status="Publisher" Owner="NLM"><PMID Version="1">32198291</PMID><DateRevised><Year>2020</Year><Month>03</Month><Day>24</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1095-9203</ISSN><JournalIssue CitedMedium="Internet"><PubDate><Year>2020</Year><Month>Mar</Month><Day>20</Day></PubDate></JournalIssue><Title>Science (New York, N.Y.)</Title><ISOAbbreviation>Science</ISOAbbreviation></Journal><ArticleTitle>Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.</ArticleTitle><ELocationID EIdType="pii" ValidYN="Y">eabb3405</ELocationID><ELocationID EIdType="doi" ValidYN="Y">10.1126/science.abb3405</ELocationID><Abstract><AbstractText>The COVID-19 pandemic caused by SARS-CoV-2 is a global health emergency. An attractive drug target among coronaviruses is the main protease (M<sup>pro</sup>, 3CL<sup>pro</sup>), due to its essential role in processing the polyproteins that are translated from the viral RNA. We report the X-ray structures of the unliganded SARS-CoV-2 M<sup>pro</sup> and its complex with an α-ketoamide inhibitor. This was derived from a previously designed inhibitor but with the P3-P2 amide bond incorporated into a pyridone ring to enhance the half-life of the compound in plasma. Based on the structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M<sup>pro</sup> The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.</AbstractText><CopyrightInformation>Copyright © 2020, American Association for the Advancement of Science.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Zhang</LastName><ForeName>Linlin</ForeName><Initials>L</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4642-9617</Identifier><AffiliationInfo><Affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lin</LastName><ForeName>Daizong</ForeName><Initials>D</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-4271-5739</Identifier><AffiliationInfo><Affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>Changchun Discovery Sciences Ltd., 789 Shunda Road, Changchun, Jilin 130012, China.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sun</LastName><ForeName>Xinyuanyuan</ForeName><Initials>X</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-2761-2862</Identifier><AffiliationInfo><Affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Curth</LastName><ForeName>Ute</ForeName><Initials>U</Initials><AffiliationInfo><Affiliation>Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Drosten</LastName><ForeName>Christian</ForeName><Initials>C</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-7923-0519</Identifier><AffiliationInfo><Affiliation>Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sauerhering</LastName><ForeName>Lucie</ForeName><Initials>L</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-5487-3243</Identifier><AffiliationInfo><Affiliation>Institute of Virology, University of Marburg, 35043 Marburg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), Marburg-Gießen-Langen Site, University of Marburg, 35043 Marburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Becker</LastName><ForeName>Stephan</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Institute of Virology, University of Marburg, 35043 Marburg, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), Marburg-Gießen-Langen Site, University of Marburg, 35043 Marburg, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rox</LastName><ForeName>Katharina</ForeName><Initials>K</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-8020-1384</Identifier><AffiliationInfo><Affiliation>Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), Hannover-Braunschweig Site, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hilgenfeld</LastName><ForeName>Rolf</ForeName><Initials>R</Initials><Identifier Source="ORCID">http://orcid.org/0000-0001-8850-2977</Identifier><AffiliationInfo><Affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany. rolf.hilgenfeld@uni-luebeck.de.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, University of Lübeck, 23562 Lübeck, Germany.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>03</Month><Day>20</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Science</MedlineTA><NlmUniqueID>0404511</NlmUniqueID><ISSNLinking>0036-8075</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>02</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>03</Month><Day>18</Day></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>3</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>3</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>3</Month><Day>22</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>aheadofprint</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32198291</ArticleId><ArticleId IdType="pii">science.abb3405</ArticleId><ArticleId IdType="doi">10.1126/science.abb3405</ArticleId></ArticleIdList></PubmedData></pubmed></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Sante/explor/CovidV2/Data/PubMed/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000186 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/PubMed/Corpus/biblio.hfd -nk 000186 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Sante
|area= CovidV2
|flux= PubMed
|étape= Corpus
|type= RBID
|clé= pubmed:32198291
|texte= Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/PubMed/Corpus/RBID.i -Sk "pubmed:32198291" \
| HfdSelect -Kh $EXPLOR_AREA/Data/PubMed/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a CovidV2
| This area was generated with Dilib version V0.6.33. |  |