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

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by 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) and basigin (BSG), are involved in high-confidence host-pathogen interactions with proteins from SARS-CoV-2. We applied the random walk with restart method on the human interactome to construct a significant sub-network around these two proteins. The protein-protein interaction sub-network captures the effects of viral invasion on fatal comorbidities through critical pathways. The ‘insulin resistance’, ‘AGE-RAGE signaling pathway in diabetic complications’ and ‘adipocytokine signaling pathway’ were found in all fatal comorbidities. The association of these critical pathways with aging and its related diseases explains the molecular basis of COVID-19 fatality. We further investigated the critical proteins and corresponding pathways, and 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 (also known as incyclinide) 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.