Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease

Babak Andi; Desigan Kumaran; Dale F Kreitler; Alexei S Soares; Jantana Keereetaweep; Jean Jakoncic; Edwin O Lazo; Wuxian Shi; Martin R Fuchs; Robert M Sweet; John Shanklin; Paul D Adams; Jurgen G Schmidt; Martha S Head; Sean McSweeney

doi:10.1038/s41598-022-15930-z

Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease

Sci Rep. 2022 Jul 16;12(1):12197. doi: 10.1038/s41598-022-15930-z.

Authors

Babak Andi^{1

2}, Desigan Kumaran^{3

4}, Dale F Kreitler⁵, Alexei S Soares⁵, Jantana Keereetaweep⁶, Jean Jakoncic⁵, Edwin O Lazo⁵, Wuxian Shi⁵, Martin R Fuchs⁵, Robert M Sweet⁵, John Shanklin⁶, Paul D Adams^{7

8

9}, Jurgen G Schmidt^{10

9}, Martha S Head^{11

9}, Sean McSweeney^{12

13

14}

Affiliations

¹ Center for BioMolecular Structure, NSLS-II, Brookhaven National Laboratory, Upton, NY, 11973, USA. bandi@bnl.gov.
² National Virtual Biotechnology Laboratory (NVBL), US Department of Energy, Washington, DC, USA. bandi@bnl.gov.
³ Biology Department, Brookhaven National Laboratory, Upton, NY, 11973, USA. kumaran@bnl.gov.
⁴ National Virtual Biotechnology Laboratory (NVBL), US Department of Energy, Washington, DC, USA. kumaran@bnl.gov.
⁵ Center for BioMolecular Structure, NSLS-II, Brookhaven National Laboratory, Upton, NY, 11973, USA.
⁶ Biology Department, Brookhaven National Laboratory, Upton, NY, 11973, USA.
⁷ Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
⁸ Department of Bioengineering, University of California, Berkeley, CA, 94720, USA.
⁹ National Virtual Biotechnology Laboratory (NVBL), US Department of Energy, Washington, DC, USA.
¹⁰ Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM, 87545, USA.
¹¹ Joint Institute for Biological Sciences, Oak Ridge National Laboratory, Oak Ridge, TN, 37831, USA.
¹² Center for BioMolecular Structure, NSLS-II, Brookhaven National Laboratory, Upton, NY, 11973, USA. smcsweeney@bnl.gov.
¹³ Biology Department, Brookhaven National Laboratory, Upton, NY, 11973, USA. smcsweeney@bnl.gov.
¹⁴ National Virtual Biotechnology Laboratory (NVBL), US Department of Energy, Washington, DC, USA. smcsweeney@bnl.gov.

Abstract

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), threatens global public health. The world needs rapid development of new antivirals and vaccines to control the current pandemic and to control the spread of the variants. Among the proteins synthesized by the SARS-CoV-2 genome, main protease (M^pro also known as 3CL^pro) is a primary drug target, due to its essential role in maturation of the viral polyproteins. In this study, we provide crystallographic evidence, along with some binding assay data, that three clinically approved anti hepatitis C virus drugs and two other drug-like compounds covalently bind to the M^pro Cys145 catalytic residue in the active site. Also, molecular docking studies can provide additional insight for the design of new antiviral inhibitors for SARS-CoV-2 using these drugs as lead compounds. One might consider derivatives of these lead compounds with higher affinity to the M^pro as potential COVID-19 therapeutics for further testing and possibly clinical trials.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antiviral Agents / therapeutic use
COVID-19 Drug Treatment*
Coronavirus 3C Proteases
Cysteine Endopeptidases / metabolism
Hepacivirus / metabolism
Humans
Molecular Docking Simulation
Protease Inhibitors / chemistry
SARS-CoV-2
Viral Nonstructural Proteins / genetics

Substances

Antiviral Agents
Protease Inhibitors
Viral Nonstructural Proteins
3C-like proteinase, SARS-CoV-2
Cysteine Endopeptidases
Coronavirus 3C Proteases

Grants and funding

P30 GM133893/GM/NIGMS NIH HHS/United States