Network-Based Analysis of Fatal Comorbidities of COVID-19 and Potential Therapeutics

Abstract

COVID-19 is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The case-fatality rate is significantly higher in older patients and those with diabetes, cancer or cardiovascular disorders. The human proteins, angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2) and basigin (BSG), are involved in high-confidence host-pathogen interactions with SARS-CoV-2 proteins. We considered these three proteins as seed nodes and applied the random walk with restart method on the human interactome to construct a protein-protein interaction sub-network, which captures the effects of viral invasion. We found that 'Insulin resistance', 'AGE-RAGE signaling in diabetic complications' and 'adipocytokine signaling' were the common pathways associated with diabetes, cancer and cardiovascular disorders. The association of these critical pathways with aging and its related diseases explains the molecular basis of COVID-19 fatality. We further identified drugs that have effects on these proteins/pathways based on gene expression studies. We particularly focused on drugs that significantly downregulate ACE2 along with other critical proteins identified by the network-based approach. Among them, COL-3 had earlier shown activity against acute lung injury and acute respiratory distress, while entinostat and mocetinostat have been investigated for non-small-cell lung cancer. We propose that these drugs can be repurposed for COVID-19.

Fig. 1.

COVID-19 host protein-protein interaction network. The receptors of SARS-CoV2, ACE2, TMPRSS2 and BSG, and the edges connecting them to their immediate neighbors are highlighted.

Fig. 2.

PPI associated with the COVID-19 infection and diseases associated with them. The dashed lines represent the protein-protein interactions.

Fig. 3.

Heterogeneous network comprising of the pathways (green triangles) responsible for fatal comorbidities related to COVID-19, genes (red circles) and drugs (as capsules) which affect them. Important proteins and corresponding significant pathways are shown. All drugs shown here are also connected with ACE2 as they downregulate ACE2 gene expression but the edges between ACE2 and the drugs are not shown here for simplicity.