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. 2021 Apr;236(4):2959-2975.
doi: 10.1002/jcp.30055. Epub 2020 Sep 22.

Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment

Na Li  1   2   3 , Lingfeng Zhao  4 , Xianquan Zhan  1   2   3   5   6
Affiliations

Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment

Na Li et al. J Cell Physiol. 2021 Apr.

Abstract

Viruses such as human cytomegalovirus (HCMV), human papillomavirus (HPV), Epstein-Barr virus (EBV), human immunodeficiency virus (HIV), and coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) represent a great burden to human health worldwide. FDA-approved anti-parasite drug ivermectin is also an antibacterial, antiviral, and anticancer agent, which offers more potentiality to improve global public health, and it can effectively inhibit the replication of SARS-CoV-2 in vitro. This study sought to identify ivermectin-related virus infection pathway alterations in human ovarian cancer cells. Stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomics was used to analyze human ovarian cancer cells TOV-21G treated with and without ivermectin (20 μmol/L) for 24 h, which identified 4447 ivermectin-related proteins in ovarian cancer cells. Pathway network analysis revealed four statistically significant antiviral pathways, including HCMV, HPV, EBV, and HIV1 infection pathways. Interestingly, compared with the reported 284 SARS-CoV-2/COVID-19-related genes from GencLip3, we identified 52 SARS-CoV-2/COVID-19-related protein alterations when treated with and without ivermectin. Protein-protein network (PPI) was constructed based on the interactions between 284 SARS-CoV-2/COVID-19-related genes and between 52 SARS-CoV-2/COVID-19-related proteins regulated by ivermectin. Molecular complex detection analysis of PPI network identified three hub modules, including cytokines and growth factor family, MAP kinase and G-protein family, and HLA class proteins. Gene Ontology analysis revealed 10 statistically significant cellular components, 13 molecular functions, and 11 biological processes. These findings demonstrate the broad-spectrum antiviral property of ivermectin benefiting for COVID-19 treatment in the context of predictive, preventive, and personalized medicine in virus-related diseases.

Keywords: SARS-CoV-2/COVID-19; ivermectin; quantitative proteomics; stable isotope labeling by amino acids in cell culture; virus-related pathways.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1
Construction of the PPI network. (a) Construction of the PPI network of 284 SARS‐CoV‐2‐related genes with a co‐expression score more than 0.7. (b–d) MCODE analysis of the entire PPI network identified three modules (module 1 score = 18, module 2 score = 11, and module 3 score = 7). (e) Construction of the PPI network of 52 ivermectin‐regulated SARS‐CoV‐2‐related proteins with co‐expression score more than 0.7. PPI, protein–protein interaction; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2
Figure 2
Figure 2
Functional and pathway enrichment analysis. (a) The biological process enrichment analysis of 52 ivermectin‐regulated SARS‐CoV‐2‐related proteins. (b) The cellular component enrichment analysis of 52 ivermectin‐regulated SARS‐CoV‐2‐related proteins. (c) The molecular function enrichment analysis of 52 ivermectin‐regulated SARS‐CoV‐2‐related proteins. Only gene sets with adjusted  p value < .05 corrected with the Benjamini–Hochberg procedure were considered significant. The less p value and more significant enrichment were shown with the greater node size. The same color indicated the same function group. Among the groups, we chose a representative of the most significant term and lag highlighted. SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2
Figure 3
Figure 3
The overlapping analysis of ivermectin‐regulated SARS‐CoV‐2‐related proteins among virus‐related pathways and their chromosomal locations. (a) The overlap of ivermectin‐regulated SARS‐CoV‐2‐related proteins among virus‐related pathways was constructed by Venn diagrams. (b) The chromosomal locations corresponding with protein expression of 52 SARS‐CoV‐2‐related proteins that were regulated by ivermectin. EBV, Epstein–Barr virus; HCMV, human cytomegalovirus; HPV, human papillomavirus; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2
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