Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.
Identifieur interne : 000442 ( new/Analysis ); précédent : 000441; suivant : 000443Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors.
Auteurs : Linlin Zhang [Allemagne] ; Daizong Lin [Allemagne] ; Xinyuanyuan Sun [Allemagne] ; Ute Curth [Allemagne] ; Christian Drosten [Allemagne] ; Lucie Sauerhering [Allemagne] ; Stephan Becker [Allemagne] ; Katharina Rox [Allemagne] ; Rolf Hilgenfeld [Allemagne]Source :
- 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
Affiliations:
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Daizong" uniqKey="Lin D" first="Daizong" last="Lin">Daizong Lin</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck</wicri:regionArea><wicri:noRegion>23562 Lübeck</wicri:noRegion><wicri:noRegion>23562 Lübeck</wicri:noRegion><wicri:noRegion>23562 Lübeck</wicri:noRegion></affiliation></author><author><name sortKey="Sun, Xinyuanyuan" sort="Sun, Xinyuanyuan" uniqKey="Sun X" first="Xinyuanyuan" last="Sun">Xinyuanyuan Sun</name><affiliation wicri:level="1"><nlm:affiliation>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of 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wicri:level="3"><nlm:affiliation>Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, Charité Universitätsmedizin Berlin, 10117 Berlin</wicri:regionArea><placeName><region type="land" nuts="3">Berlin</region><settlement type="city">Berlin</settlement></placeName></affiliation></author><author><name sortKey="Sauerhering, Lucie" sort="Sauerhering, Lucie" uniqKey="Sauerhering L" first="Lucie" last="Sauerhering">Lucie Sauerhering</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Virology, University of Marburg, 35043 Marburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Marburg, 35043 Marburg</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Giessen</region><settlement type="city">Marbourg</settlement></placeName></affiliation></author><author><name sortKey="Becker, Stephan" sort="Becker, Stephan" uniqKey="Becker S" first="Stephan" last="Becker">Stephan Becker</name><affiliation wicri:level="3"><nlm:affiliation>Institute of Virology, University of Marburg, 35043 Marburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Virology, University of Marburg, 35043 Marburg</wicri:regionArea><placeName><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Giessen</region><settlement type="city">Marbourg</settlement></placeName></affiliation></author><author><name sortKey="Rox, Katharina" sort="Rox, Katharina" uniqKey="Rox K" first="Katharina" last="Rox">Katharina Rox</name><affiliation wicri:level="1"><nlm:affiliation>Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), Inhoffenstraße 7, 38124 Braunschweig</wicri:regionArea><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion><wicri:noRegion>38124 Braunschweig</wicri:noRegion></affiliation></author><author><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><affiliation wicri:level="1"><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><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, 23562 Lübeck</wicri:regionArea><wicri:noRegion>23562 Lübeck</wicri:noRegion><wicri:noRegion>23562 Lübeck</wicri:noRegion><wicri:noRegion>23562 Lübeck</wicri:noRegion></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><affiliations><list><country><li>Allemagne</li></country><region><li>Basse-Saxe</li><li>Berlin</li><li>District de Giessen</li><li>Hesse (Land)</li></region><settlement><li>Berlin</li><li>Hanovre</li><li>Marbourg</li></settlement></list><tree><country name="Allemagne"><noRegion><name sortKey="Zhang, Linlin" sort="Zhang, Linlin" uniqKey="Zhang L" first="Linlin" last="Zhang">Linlin Zhang</name></noRegion><name sortKey="Becker, Stephan" sort="Becker, Stephan" uniqKey="Becker S" first="Stephan" last="Becker">Stephan Becker</name><name sortKey="Curth, Ute" sort="Curth, Ute" uniqKey="Curth U" first="Ute" last="Curth">Ute Curth</name><name sortKey="Drosten, Christian" sort="Drosten, Christian" uniqKey="Drosten C" first="Christian" last="Drosten">Christian Drosten</name><name sortKey="Hilgenfeld, Rolf" sort="Hilgenfeld, Rolf" uniqKey="Hilgenfeld R" first="Rolf" last="Hilgenfeld">Rolf Hilgenfeld</name><name sortKey="Lin, Daizong" sort="Lin, Daizong" uniqKey="Lin D" first="Daizong" last="Lin">Daizong Lin</name><name sortKey="Rox, Katharina" sort="Rox, Katharina" uniqKey="Rox K" first="Katharina" last="Rox">Katharina Rox</name><name sortKey="Sauerhering, Lucie" sort="Sauerhering, Lucie" uniqKey="Sauerhering L" first="Lucie" last="Sauerhering">Lucie Sauerhering</name><name sortKey="Sun, Xinyuanyuan" sort="Sun, Xinyuanyuan" uniqKey="Sun X" first="Xinyuanyuan" last="Sun">Xinyuanyuan Sun</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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