Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors

Linlin Zhang; Daizong Lin; Xinyuanyuan Sun; Ute Curth; Christian Drosten; Lucie Sauerhering; Stephan Becker; Katharina Rox; Rolf Hilgenfeld

doi:10.1126/science.abb3405

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors

Linlin Zhang, Daizong Lin, Xinyuanyuan Sun, Ute Curth, Christian Drosten, Lucie Sauerhering, Stephan Becker, Katharina Rox, Rolf Hilgenfeld^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Biochemie

515 Zitate (Scopus)

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (M^pro, also called 3CL^pro) because of 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^pro and its complex with an a-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. On the basis of the unliganded structure, we developed the lead compound into a potent inhibitor of the SARS-CoV-2 M^pro. The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route.

Originalsprache	Englisch
Zeitschrift	Science
Jahrgang	368
Ausgabenummer	6489
Seiten (von - bis)	409-412
Seitenumfang	4
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.abb3405
Publikationsstatus	Veröffentlicht - 24.04.2020

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

DFG-Fachsystematik

2.11-01 Biochemie

Coronavirus-Bezug

Forschung zu SARS-CoV-2 / COVID-19

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

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10.1126/science.abb3405

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title = "Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors",

abstract = "The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of 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 a-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. On the basis of the unliganded 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.",

author = "Linlin Zhang and Daizong Lin and Xinyuanyuan Sun and Ute Curth and Christian Drosten and Lucie Sauerhering and Stephan Becker and Katharina Rox and Rolf Hilgenfeld",

note = "Funding Information: We thank Y. Kusov and G. Hansen, as well as A. Aljnabi, for determining the inhibitory activities of compounds in a SARS-CoV replicon and against recombinant MERS-CoV Mpro, respectively; T. Biet for recording 13C NMR spectra; A. Ahlers, J. Schreiber, and L. Litz for excellent technical assistance; K. Chen for continuous organizational support; and the staff at beamline 14.2 of BESSY II, Berlin, Germany, for help with diffraction data collection. Funding: We thank the German Center for Infection Research (DZIF) for financial support (projects TTU01, grant 8011801806, and TTU09, grant 8004709710). Author contributions: Conceptualization: Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",

year = "2020",

month = apr,

day = "24",

doi = "10.1126/science.abb3405",

language = "English",

volume = "368",

pages = "409--412",

journal = "Science",

issn = "0036-8075",

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AU - Zhang, Linlin

AU - Lin, Daizong

AU - Sun, Xinyuanyuan

AU - Curth, Ute

AU - Drosten, Christian

AU - Sauerhering, Lucie

AU - Becker, Stephan

AU - Rox, Katharina

AU - Hilgenfeld, Rolf

N1 - Funding Information: We thank Y. Kusov and G. Hansen, as well as A. Aljnabi, for determining the inhibitory activities of compounds in a SARS-CoV replicon and against recombinant MERS-CoV Mpro, respectively; T. Biet for recording 13C NMR spectra; A. Ahlers, J. Schreiber, and L. Litz for excellent technical assistance; K. Chen for continuous organizational support; and the staff at beamline 14.2 of BESSY II, Berlin, Germany, for help with diffraction data collection. Funding: We thank the German Center for Infection Research (DZIF) for financial support (projects TTU01, grant 8011801806, and TTU09, grant 8004709710). Author contributions: Conceptualization: Publisher Copyright: © 2020 American Association for the Advancement of Science. All rights reserved. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.

PY - 2020/4/24

Y1 - 2020/4/24

N2 - The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of 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 a-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. On the basis of the unliganded 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.

AB - The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is a global health emergency. An attractive drug target among coronaviruses is the main protease (Mpro, also called 3CLpro) because of 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 a-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. On the basis of the unliganded 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.

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Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors

Abstract

Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

Coronavirus-Bezug

UN SDGs

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