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^*

^*Corresponding author for this work

Institute of Biochemistry

515 Citations (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.

Original language	English
Journal	Science
Volume	368
Issue number	6489
Pages (from-to)	409-412
Number of pages	4
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.abb3405
Publication status	Published - 24.04.2020

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

DFG Research Classification Scheme

2.11-01 Biochemistry

Coronavirus related work

Research on SARS-CoV-2 / COVID-19

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1126/science.abb3405

Cite this

@article{b7207d3fba4d47ee810653a25e63ccb3,

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",

number = "6489",

}

TY - JOUR

T1 - Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors

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.

UR - http://www.scopus.com/inward/record.url?scp=85083001642&partnerID=8YFLogxK

U2 - 10.1126/science.abb3405

DO - 10.1126/science.abb3405

M3 - Journal articles

C2 - 32198291

AN - SCOPUS:85083001642

SN - 0036-8075

VL - 368

SP - 409

EP - 412

JO - Science

JF - Science

IS - 6489

ER -

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

Abstract

Research Areas and Centers

DFG Research Classification Scheme

Coronavirus related work

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this