Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay

Wenyue Cao; Chia Chuan Dean Cho; Zhi Zachary Geng; Namir Shaabani; Xinyu R. Ma; Erol C. Vatansever; Yugendar R. Alugubelli; Yuying Ma; Sankar P. Chaki; William H. Ellenburg; Kai S. Yang; Yuchen Qiao; Robert Allen; Benjamin W. Neuman; Henry Ji; Shiqing Xu; Wenshe Ray Liu

doi:10.1021/acscentsci.1c00910

Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay

Wenyue Cao
, Chia Chuan Dean Cho
, Zhi Zachary Geng
, Namir Shaabani
, Xinyu R. Ma
, Erol C. Vatansever
, Yugendar R. Alugubelli
, Yuying Ma
, Sankar P. Chaki
, William H. Ellenburg
, Kai S. Yang
, Yuchen Qiao
, Robert Allen
, Benjamin W. Neuman
, Henry Ji^*
, Shiqing Xu^*
, Wenshe Ray Liu^*

^*Corresponding author for this work

Texas A&M University
Sorrento Therapeutics

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

48 Scopus citations

Abstract

As an essential enzyme of SARS-CoV-2, main protease (M^Pro) triggers acute toxicity to its human cell host, an effect that can be alleviated by an M^Pro inhibitor. Using this toxicity alleviation, we developed an effective method that allows a bulk analysis of the cellular potency of M^Pro inhibitors. This novel assay is advantageous over an antiviral assay in providing precise cellular M^Pro inhibition information to assess an M^Pro inhibitor. We used this assay to analyze 30 known M^Pro inhibitors. Contrary to their strong antiviral effects and up to 10 μM, 11a, calpain inhibitor II, calpain XII, ebselen, bepridil, chloroquine, and hydroxychloroquine showed relatively weak to undetectable cellular M^Pro inhibition potency implicating their roles in interfering with key steps other than just the M^Pro catalysis in the SARS-CoV-2 life cycle. Our results also revealed that MPI5, MPI6, MPI7, and MPI8 have high cellular and antiviral potency. As the one with the highest cellular and antiviral potency among all tested compounds, MPI8 has a remarkable cellular M^Pro inhibition IC₅₀ value of 31 nM that matches closely to its strong antiviral effect with an EC₅₀ value of 30 nM. Therefore, we cautiously suggest exploring MPI8 further for COVID-19 preclinical tests.

Original language	English
Pages (from-to)	192-204
Number of pages	13
Journal	ACS Central Science
Volume	8
Issue number	2
DOIs	https://doi.org/10.1021/acscentsci.1c00910
State	Published - 23 Feb 2022
Externally published	Yes

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Cao, W., Cho, C. C. D., Geng, Z. Z., Shaabani, N., Ma, X. R., Vatansever, E. C., Alugubelli, Y. R., Ma, Y., Chaki, S. P., Ellenburg, W. H., Yang, K. S., Qiao, Y., Allen, R., Neuman, B. W., Ji, H., Xu, S., & Liu, W. R. (2022). Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay. ACS Central Science, 8(2), 192-204. https://doi.org/10.1021/acscentsci.1c00910

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title = "Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay",

abstract = "As an essential enzyme of SARS-CoV-2, main protease (MPro) triggers acute toxicity to its human cell host, an effect that can be alleviated by an MPro inhibitor. Using this toxicity alleviation, we developed an effective method that allows a bulk analysis of the cellular potency of MPro inhibitors. This novel assay is advantageous over an antiviral assay in providing precise cellular MPro inhibition information to assess an MPro inhibitor. We used this assay to analyze 30 known MPro inhibitors. Contrary to their strong antiviral effects and up to 10 μM, 11a, calpain inhibitor II, calpain XII, ebselen, bepridil, chloroquine, and hydroxychloroquine showed relatively weak to undetectable cellular MPro inhibition potency implicating their roles in interfering with key steps other than just the MPro catalysis in the SARS-CoV-2 life cycle. Our results also revealed that MPI5, MPI6, MPI7, and MPI8 have high cellular and antiviral potency. As the one with the highest cellular and antiviral potency among all tested compounds, MPI8 has a remarkable cellular MPro inhibition IC50 value of 31 nM that matches closely to its strong antiviral effect with an EC50 value of 30 nM. Therefore, we cautiously suggest exploring MPI8 further for COVID-19 preclinical tests.",

author = "Wenyue Cao and Cho, \{Chia Chuan Dean\} and Geng, \{Zhi Zachary\} and Namir Shaabani and Ma, \{Xinyu R.\} and Vatansever, \{Erol C.\} and Alugubelli, \{Yugendar R.\} and Yuying Ma and Chaki, \{Sankar P.\} and Ellenburg, \{William H.\} and Yang, \{Kai S.\} and Yuchen Qiao and Robert Allen and Neuman, \{Benjamin W.\} and Henry Ji and Shiqing Xu and Liu, \{Wenshe Ray\}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Published by American Chemical Society",

year = "2022",

month = feb,

day = "23",

doi = "10.1021/acscentsci.1c00910",

language = "英语",

volume = "8",

pages = "192--204",

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AU - Cao, Wenyue

AU - Cho, Chia Chuan Dean

AU - Geng, Zhi Zachary

AU - Shaabani, Namir

AU - Ma, Xinyu R.

AU - Vatansever, Erol C.

AU - Alugubelli, Yugendar R.

AU - Ma, Yuying

AU - Chaki, Sankar P.

AU - Ellenburg, William H.

AU - Yang, Kai S.

AU - Qiao, Yuchen

AU - Allen, Robert

AU - Neuman, Benjamin W.

AU - Ji, Henry

AU - Xu, Shiqing

AU - Liu, Wenshe Ray

PY - 2022/2/23

Y1 - 2022/2/23

N2 - As an essential enzyme of SARS-CoV-2, main protease (MPro) triggers acute toxicity to its human cell host, an effect that can be alleviated by an MPro inhibitor. Using this toxicity alleviation, we developed an effective method that allows a bulk analysis of the cellular potency of MPro inhibitors. This novel assay is advantageous over an antiviral assay in providing precise cellular MPro inhibition information to assess an MPro inhibitor. We used this assay to analyze 30 known MPro inhibitors. Contrary to their strong antiviral effects and up to 10 μM, 11a, calpain inhibitor II, calpain XII, ebselen, bepridil, chloroquine, and hydroxychloroquine showed relatively weak to undetectable cellular MPro inhibition potency implicating their roles in interfering with key steps other than just the MPro catalysis in the SARS-CoV-2 life cycle. Our results also revealed that MPI5, MPI6, MPI7, and MPI8 have high cellular and antiviral potency. As the one with the highest cellular and antiviral potency among all tested compounds, MPI8 has a remarkable cellular MPro inhibition IC50 value of 31 nM that matches closely to its strong antiviral effect with an EC50 value of 30 nM. Therefore, we cautiously suggest exploring MPI8 further for COVID-19 preclinical tests.

AB - As an essential enzyme of SARS-CoV-2, main protease (MPro) triggers acute toxicity to its human cell host, an effect that can be alleviated by an MPro inhibitor. Using this toxicity alleviation, we developed an effective method that allows a bulk analysis of the cellular potency of MPro inhibitors. This novel assay is advantageous over an antiviral assay in providing precise cellular MPro inhibition information to assess an MPro inhibitor. We used this assay to analyze 30 known MPro inhibitors. Contrary to their strong antiviral effects and up to 10 μM, 11a, calpain inhibitor II, calpain XII, ebselen, bepridil, chloroquine, and hydroxychloroquine showed relatively weak to undetectable cellular MPro inhibition potency implicating their roles in interfering with key steps other than just the MPro catalysis in the SARS-CoV-2 life cycle. Our results also revealed that MPI5, MPI6, MPI7, and MPI8 have high cellular and antiviral potency. As the one with the highest cellular and antiviral potency among all tested compounds, MPI8 has a remarkable cellular MPro inhibition IC50 value of 31 nM that matches closely to its strong antiviral effect with an EC50 value of 30 nM. Therefore, we cautiously suggest exploring MPI8 further for COVID-19 preclinical tests.

UR - https://www.scopus.com/pages/publications/85124580536

U2 - 10.1021/acscentsci.1c00910

DO - 10.1021/acscentsci.1c00910

M3 - 文章

AN - SCOPUS:85124580536

SN - 2374-7943

VL - 8

SP - 192

EP - 204

JO - ACS Central Science

JF - ACS Central Science

IS - 2

ER -

Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay

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