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X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Katharina Rox, View ORCID ProfileRolf Hilgenfeld
doi: https://doi.org/10.1101/2020.02.17.952879
Linlin Zhang
1Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
2German Center for Infection Research (DZIF), Hamburg - Lübeck - Borstel - Riems Site, University of Lübeck, 23562 Lübeck, Germany
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Daizong Lin
1Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
3Changchun Discovery Sciences, 789 Shunda Rd., Changchun, Jilin 130012, China
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Xinyuanyuan Sun
1Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
2German Center for Infection Research (DZIF), Hamburg - Lübeck - Borstel - Riems Site, University of Lübeck, 23562 Lübeck, Germany
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Katharina Rox
4Department of Chemical Biology, Helmholtz Center for Infection Research (HZI), Inhoffenstraße 7, 38124 Braunschweig, Germany
5German Center for Infection Research (DZIF), Hannover – Braunschweig Site, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany
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Rolf Hilgenfeld
1Institute of Biochemistry, Center for Structural and Cell Biology in Medicine, University of Lübeck, Ratzeburger Allee 160, 23562 Lübeck, Germany
2German Center for Infection Research (DZIF), Hamburg - Lübeck - Borstel - Riems Site, University of Lübeck, 23562 Lübeck, Germany
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  • ORCID record for Rolf Hilgenfeld
  • For correspondence: rolf.hilgenfeld@uni-luebeck.de
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Abstract

A novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also called 3CLpro) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro at 1.75 Å resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-Å crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.

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Posted February 20, 2020.
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X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors
Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Katharina Rox, Rolf Hilgenfeld
bioRxiv 2020.02.17.952879; doi: https://doi.org/10.1101/2020.02.17.952879
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X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors
Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Katharina Rox, Rolf Hilgenfeld
bioRxiv 2020.02.17.952879; doi: https://doi.org/10.1101/2020.02.17.952879

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