Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2021 Jun 1;6(1):214.
doi: 10.1038/s41392-021-00639-8.

Identification of proteasome and caspase inhibitors targeting SARS-CoV-2 Mpro

Zhengyuan Wang #  1 , Yao Zhao #  2 , Qingxing Wang #  3 , Yangfei Xing #  1 , Lu Feng  2 , Juan Kong  2 , Chao Peng  4 , Leike Zhang  5 , Haitao Yang  6 , Min Lu  7
Affiliations
Comment

Identification of proteasome and caspase inhibitors targeting SARS-CoV-2 Mpro

Zhengyuan Wang et al. Signal Transduct Target Ther. .
No abstract available

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Identification of MG132 and Z-VAD(OMe)-FMK as inhibitors targeting SARS-CoV-2 Mpro.
a Dot profile showing the change of Tm (ΔTm) of SARS-CoV-2 Mpro upon incubation with 4198 compounds in the pilot DSF screening (n = 1). Values in brackets show the ΔTm induced by the indicated compounds. The top five stabilizing and destabilizing hits are shown. b Bar graph showing the ΔTm of Mpro induced by the 36 studied compounds (1:10 molar ratio of Mpro:compound). c Close-up view of the binding mode of MG132 in the active site of SARS-CoV-2 Mpro. The Mpro residues involved in MG132 binding are shown as pale cyan sticks. Hydrogen bonds are indicated with dashed lines. d Comparison of the binding mode of MG132 in the active site of SARS-CoV-2 Mpro with those of 11a (PDB code: 6LZE), 11b (PDB code: 6M0K), GC376 (PDB code: 6WTT), and N3 (PDB code: 6LU7). e Summarized binding mode of MG132 in the active site of SARS-CoV-2 Mpro. The pink areas represent hydrophobic interaction networks between Mpro subsites and MG132. f Close-up view of the binding mode of Z-VAD(OMe)-FMK in the active site of SARS-CoV-2 Mpro. The residues involved in Z-VAD(OMe)-FMK binding are shown as beige sticks. Hydrogen bonds are indicated with dashed lines. g Comparison of the binding mode of Z-VAD(OMe)-FMK in the active site of SARS-CoV-2 Mpro with those of 11a (PDB code: 6LZE), 11b (PDB code: 6M0K), GC376 (PDB code: 6WTT), and N3 (PDB code: 6LU7). h Summarized binding mode of Mpro-Z-VAD(OMe)-FMK. The red labels represent the unique binding features. i The hydrolytic activity of SARS-CoV-2 Mpro was measured in the presence of increasing concentrations of the indicated compounds. The IC50 values were determined based on dose–response curves using nonlinear regression. The data represent mean ± SEM from 3 experiments. The y-axis of the graphs represents mean % inhibition of hydrolytic activity. j Antiviral activity against SARS-CoV-2 and cytotoxicity of the indicated compounds in Vero cells. Vero cells were treated with a concentration series of the indicated compounds and infected with SARS-CoV-2 (MOI = 0.01). At 24 h post-infection, the virions in the culture supernatant were harvested, followed by determination of the viral RNA copy number by qRT-PCR. The cytotoxicity of the indicated compounds in Vero cells was determined using the CCK8 assay. The y-axes of the graphs represent mean % reduction of the virion yield or mean % cell viability.
See this image and copyright information in PMC

Comment on

  • SARS-CoV-2 Mpro inhibitors with antiviral activity in a transgenic mouse model.
    Qiao J, Li YS, Zeng R, Liu FL, Luo RH, Huang C, Wang YF, Zhang J, Quan B, Shen C, Mao X, Liu X, Sun W, Yang W, Ni X, Wang K, Xu L, Duan ZL, Zou QC, Zhang HL, Qu W, Long YH, Li MH, Yang RC, Liu X, You J, Zhou Y, Yao R, Li WP, Liu JM, Chen P, Liu Y, Lin GF, Yang X, Zou J, Li L, Hu Y, Lu GW, Li WM, Wei YQ, Zheng YT, Lei J, Yang S. Qiao J, et al. Science. 2021 Mar 26;371(6536):1374-1378. doi: 10.1126/science.abf1611. Epub 2021 Feb 18. Science. 2021. PMID: 33602867 Free PMC article.

References

    1. Jin Z, et al. Structure of M(pro) from SARS-CoV-2 and discovery of its inhibitors. Nature. 2020;582:289–293. doi: 10.1038/s41586-020-2223-y. - DOI - PubMed
    1. Dai W, et al. Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science. 2020;368:1331–1335. doi: 10.1126/science.abb4489. - DOI - PMC - PubMed
    1. Ma C, et al. Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease. Cell Res. 2020;30:678–692. doi: 10.1038/s41422-020-0356-z. - DOI - PMC - PubMed
    1. Chen S, et al. Arsenic trioxide rescues structural p53 mutations through a cryptic allosteric site. Cancer cell. 2021;39:225–239.e8. doi: 10.1016/j.ccell.2020.11.013. - DOI - PubMed
    1. Qiao J, et al. SARS-CoV-2 M(pro) inhibitors with antiviral activity in a transgenic mouse model. Science. 2021;371:1374–1378. doi: 10.1126/science.abf1611. - DOI - PMC - PubMed