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

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

Biochemistry and Cell Biology

Brookhaven National Laboratory
United States Department of Energy
Lawrence Berkeley National Laboratory
University of California at Berkeley
Los Alamos National Laboratory
Oak Ridge National Laboratory

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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.

Original language	English
Article number	12197
Journal	Scientific Reports
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41598-022-15930-z
State	Published - Dec 2022

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Andi, B., Kumaran, D., Kreitler, D. F., Soares, A. S., Keereetaweep, J., Jakoncic, J., Lazo, E. O., Shi, W., Fuchs, M. R., Sweet, R. M., Shanklin, J., Adams, P. D., Schmidt, J. G., Head, M. S., & McSweeney, S. (2022). Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease. Scientific Reports, 12(1), Article 12197. https://doi.org/10.1038/s41598-022-15930-z

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

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 (Mpro also known as 3CLpro) 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 Mpro 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 Mpro as potential COVID-19 therapeutics for further testing and possibly clinical trials.",

author = "Babak Andi and Desigan Kumaran and Kreitler, \{Dale F.\} and Soares, \{Alexei S.\} and Jantana Keereetaweep and Jean Jakoncic and Lazo, \{Edwin O.\} and Wuxian Shi and Fuchs, \{Martin R.\} and Sweet, \{Robert M.\} and John Shanklin and Adams, \{Paul D.\} and Schmidt, \{Jurgen G.\} and Head, \{Martha S.\} and Sean McSweeney",

note = "Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

year = "2022",

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doi = "10.1038/s41598-022-15930-z",

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Andi, B, Kumaran, D, Kreitler, DF, Soares, AS, Keereetaweep, J, Jakoncic, J, Lazo, EO, Shi, W, Fuchs, MR, Sweet, RM, Shanklin, J, Adams, PD, Schmidt, JG, Head, MS & McSweeney, S 2022, 'Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease', Scientific Reports, vol. 12, no. 1, 12197. https://doi.org/10.1038/s41598-022-15930-z

TY - JOUR

T1 - Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease

AU - Andi, Babak

AU - Kumaran, Desigan

AU - Kreitler, Dale F.

AU - Soares, Alexei S.

AU - Keereetaweep, Jantana

AU - Jakoncic, Jean

AU - Lazo, Edwin O.

AU - Shi, Wuxian

AU - Fuchs, Martin R.

AU - Sweet, Robert M.

AU - Shanklin, John

AU - Adams, Paul D.

AU - Schmidt, Jurgen G.

AU - Head, Martha S.

AU - McSweeney, Sean

PY - 2022/12

Y1 - 2022/12

N2 - 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 (Mpro also known as 3CLpro) 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 Mpro 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 Mpro as potential COVID-19 therapeutics for further testing and possibly clinical trials.

AB - 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 (Mpro also known as 3CLpro) 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 Mpro 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 Mpro as potential COVID-19 therapeutics for further testing and possibly clinical trials.

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JO - Scientific Reports

JF - Scientific Reports

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ER -

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

Abstract

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