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

被引：36

作者：

Cao, Wenyue ^{[1
]}

Cho, Chia-Chuan Dean ^{[1
]}

Geng, Zhi Zachary ^{[1
]}

Shaabani, Namir ^{[2
]}

Ma, Xinyu R. ^{[1
]}

Vatansever, Erol C. ^{[1
]}

Alugubelli, Yugendar R. ^{[1
]}

Ma, Yuying ^{[1
]}

Chaki, Sankar P. ^{[3
]}

Ellenburg, William H. ^{[1
]}

Yang, Kai S. ^{[1
]}

Qiao, Yuchen ^{[1
]}

Allen, Robert ^{[2
]}

Neuman, Benjamin W. ^{[3
]}

Ji, Henry ^{[2
]}

Xu, Shiqing ^{[1
]}

Liu, Wenshe Ray ^{[1
,4
,5
,6
,7
]}

机构：

[1] Texas A&M Univ, Dept Chem, Texas A&M Drug Discovery Lab, College Stn, TX 77843 USA

[2] Sorrento Therapeut Inc, San Diego, CA 92121 USA

[3] Texas A&M Univ, Dept Biol, College Stn, TX 77843 USA

[4] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA

[5] Texas A&M Univ, Dept Mol & Cellular Med, Coll Med, College Stn, TX 77843 USA

[6] Texas A&M Univ, Inst Biosci & Technol, Coll Med, Houston, TX 77030 USA

[7] Texas A&M Univ, Dept Translat Med Sci, Coll Med, Houston, TX 77030 USA

来源：

ACS CENTRAL SCIENCE | 2022年 / 8卷 / 02期

关键词：

Life cycle - Toxicity;

D O I：

10.1021/acscentsci.1c00910

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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 mu M, 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.

引用

页码：192 / 204

页数：13

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