COVID-19 broke up in 2019 at Wuhan, Hubei Province of China and spreads over the world at a horrific speed. The pathogen of COVID-19 is named as SARS-CoV-2, who had 82% nucleotide identity with SARS-CoV. From the clinical data, COVID-19 manifests with fever, nonproductive cough, dyspnea, myalgia, fatigue, normal or decreased leukocyte counts, and severe lung injury. The sereve or death cases also showed organ dysfunction, including shock, acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, liver dysfunction and secondary inflammation[3, 21–23]Therefore, it is urgent to find out effective strategies to protect the organ and reduce the mortality rate.
The same as SARS-CoV, SARS-CoV-2 also invades into host by combining with ACE2. It is reported SARS-CoV can inhibit the expression of ACE2 after infection. ACE2 is a carboxymonopeptidase which acts like the antagonist of angiotensin. The renin-angiotensin system (RAS) exacerbates pulmonary hypertension, acute lung injury and experimental lung fibrosis. So ACE2 plays an protective role in lung infection.
Recently, many studies reported that SARS-CoV-2 could not only infect host through respiratory tract,but also gastrointestinal tract. ACE2 protects intestinal from inflammation induced by epithelial damage. It is a key regulator of dietary amino acid homeostasis, innate immunity, gut microbial ecology. SARS-CoV-2 may reduce the expression of ACE2 when infected through intestinal tract just like SARS-CoV. So it is reasonable to find drugs recovering the function of genes co-expressed with ACE2, by which we can prevent the development and infection of COVID-19.
The genes co-expressed with ACE2 in the colonic epithelial cells was acquired from Jun et al. We selected 125 hub genes from them and constructed a PPI network. The cluster analysis was performed to figure out the main network and correlation between these genes. Two clusters were obtained. Genes of cluster 1 were mainly about immune response such as CCR10, GPR31, F2RL1 and neurotransmission such as PNOC, NPFFR2, NPY. Genes of cluster 2 were mainly about ribosome assembling. It supported the view that ACE2 played an important role in defending against virus infection by means of intensifying immune response or interfering ribosome normal function to decrease the replication of virus. The GO analysis and the KEGG pathway revealed these genes were aggregated in ribosome, exosomes, extracellular cellular components; structure constituent of ribosome, G-protein coupled receptor activity, MHC class I and II receptor activity biological processes; immune response, protein metabolism, signal transduction biological processes; and ribosome, graft-versus-host disease, viral myocarditis pathways.
After uploading the genes co-expressed with ACE2 in the colonic epithelial cells to the Cmap database, we got two potential drugs (ikarugamycin and molsidomine) which positively correlated with our gene profiles. Ikarugamycin is a previously discovered antibiotic, however it has been found to inhibit clathrin-mediated endocytosis. Most virus depend on endocytic uptake to get into cells, one way of which is the internalization involving clathrin-mediated endocytosis. Surprisingly, there is a report about SARS-CoV invading into host cells depending on clathrin-mediated endocytosis. So ikarugamycin is possibly to treat COVID-19. Molsidomine is an orally active, long-acting vasodilator. It is a nitric oxide (NO) donor and there is a case that inhalation of NO alleviated the symptom of severe acute respiratory syndrome (SARS). It is also reported that NO inhibited the replication cycle of SARS-CoV. Inhaled NO achieves selective vasodilation of the pulmonary circulation, which contributes to the improvement of ventilation-perfusion matching and oxygenation in patients with acute respiratory distress syndrome. Moreover, inhibition of AngII receptor type 1 attenuated acute severe lung injury and pulmonary edema caused by the protein of SARS-CoV. The same as SARS, COVID-19 also showed progressive dyspnoea and lung field shadowing. According to the pathology of COVID-19, the lung tissue displayed pulmonary oedema and desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome[33, 34]. Therefore, molsidomine is potential to alleviate the symptom of COVID-19.