Network for network concept offers new insights into host- SARS-CoV-2 protein interactions and potential novel targets for developing antiviral drugs

Abstract

SARS-CoV-2, the causal agent of COVID-19, is primarily a pulmonary virus that can directly or indirectly infect several organs. Despite many studies carried out during the current COVID-19 pandemic, some pathological features of SARS-CoV-2 have remained unclear. It has been recently attempted to address the current knowledge gaps on the viral pathogenicity and pathological mechanisms via cellular-level tropism of SARS-CoV-2 using human proteomics, visualization of virus-host protein-protein interactions (PPIs), and enrichment analysis of experimental results. The synergistic use of models and methods that rely on graph theory has enabled the visualization and analysis of the molecular context of virus/host PPIs. We review current knowledge on the SARS-COV-2/host interactome cascade involved in the viral pathogenicity through the graph theory concept and highlight the hub proteins in the intra-viral network that create a subnet with a small number of host central proteins, leading to cell disintegration and infectivity. Then we discuss the putative principle of the "gene-for-gene and "network for network" concepts as platforms for future directions toward designing efficient anti-viral therapies.

Keywords: Gene network; Protein-protein interactions; SARS-CoV-2; Virus-host interactome.

Fig. 1

SARS-CoV-2 genome annotation showing position and relative size of ORFs of 4 structural proteins, 16 non-structural proteins and 9 accessory factors. Fig. 1 was illustrated using Adobe Photoshop 2021 v 22.2. nt = nucleotide.

Fig. 2

SARS-CoV-2 protein-protein interactions were retrieved from the previously reported experimental method [13]. Orf10 followed by NSP16, M, orf7a and orf7b show a higher degree of intra-viral PPIs. The network was created using Cytoscape 3.8.

Fig. 3

Gene Ontology (GO) analysis was performed on CoV-2-interacted host proteins. GO-terms for biological processes were obtained from the STRING database for analysis in the BiNGO tool: a Cytoscape plugin. Significant GO terms (5% FDR) were identified and further refined to select non-redundant terms.

Fig. 4

Human protein interactors as a candidate for SARS-CoV-2 proteins collected from the previously reported experimental methods [13,52,72,115,120]. The network was created using Cytoscape 3.8. Red node: hub node that shows a higher degree of human-human PPIs.

Fig. 5

Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis was performed on the hub nodes of human-human PPIs [13,52,72,115,120]. The CytoKEGG plugin was used to import the pathways into the Cytoscape 3.8 software.

Fig. 6

Merge of SARS-CoV-2 proteins network and human proteins network showing network for network theory. Intra-viral and Hu-CoV-2 protein interactions were experimentally verified in previously published data [13,52,115,120]. The network was created using Cytoscape 3.8. Blue node: human protein. Red node: virus protein.