The common regulatory pathway of COVID-19 and multiple inflammatory diseases and the molecular mechanism of cepharanthine in the treatment of COVID-19

Abstract

Background: Similar pathogenesis makes Corona Virus Disease 2019 (COVID-19) associated with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and gouty arthritis (GA), and it is possible to introduce common drugs for the treatment of RA, AS and GA into the treatment of COVID-19. That is, "homotherapy for heteropathy", especially cytokine inhibitors. But little is known about the specific link between the diseases. In addition, "new use of old drugs" is an important short-term strategy for the treatment of COVID-19. Cepharanthine (CEP), a monomer component of traditional Chinese medicine (TCM), is mainly used in the treatment of leukopenia and has recently been proved to have a good therapeutic effect on COVID-19, but its specific molecular mechanism has not been clearly explained. The purpose of this work is to explore the common targets and signaling pathways among COVID-19, RA, AS, and GA by means of network pharmacology (NP), and to infer the potential mechanism of CEP in the treatment of COVID-19. Methods: Firstly, SwissTargetPrediction was used to predict the targets of CEP, and the pathogenic targets of COVID-19, RA, AS and GA were searched in GeneCards, OMIM, TTD, PharmGKB database and literature, respectively. Then, the protein interaction network of CEP and COVID-19 cross targets and the common targets of COVID-19, RA, AS and GA was constructed. Cytosscape 3.7.2 software was used to construct CEP-common targets-signaling pathways-COVID-19 network, module function analysis, gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG). Finally, the molecular docking of hub targets and CEP was carried out by AutoDock software. Results: The results showed that the common targets of the four diseases were tumor necrosis factor (TNF), interleukin (IL)-6 and IL-1β, and involved Coronavirus disease, IL-17 signaling pathway and TNF signaling pathway. CEP has a good binding force with AKT Serine/Threonine Kinase 1 (AKT1), phosphatidylinositol 3-kinase (PIK3) CA, PIK3CD and Angiotensin-converting enzyme 2 (ACE2), and plays a role in the treatment of COVID-19 by regulating PI3K-Akt signaling pathway, Relaxin signaling pathway, VEGF signaling pathway and HIF-1 signaling pathway. Conclusion: Therefore, this study not only confirmed the potential mechanism of CEP in the treatment of COVID-19 at the molecular level, but also found that TNF and IL-17 inhibitors, which are commonly used in the treatment of RA, AS and GA, may also affect the treatment of COVID-19, which provides new clues and theoretical basis for the rapid discovery of effective therapeutic drugs for COVID-19.

Keywords: COVID-19; cepharanthine; homotherapy for heteropathy; network pharmacology; new use of old drugs.

FIGURE 1

Workflow diagram of the NP.

FIGURE 2

The common hub targets and GO process of single disease (COVID-19) and multiple disease combinations (COVID-19, RA, AS, GA). (A) Multi-disease combination (COVID-19, RA, AS, GA) 99 common targets. (B) Single disease (COVID-19) targets ranked TOP10 targets (left), multi-disease combination (COVID-19, RA, AS, GA) common targets ranked TOP10 targets (right), the intersection of the two, five common targets were obtained: TNF, IL-6, IL-1β, CD4 and ALB, these five targets not only play a central role in the pathogenesis and progression of single disease (COVID-19), but also are potential targets for the treatment of RA, AS and GA. (C) The common GO process involved in multiple disease combinations (COVID-19, RA, AS, GA). (D) The GO process involved in single disease (COVID-19). (E) The common GO process obtained by the intersection analysis of single disease (COVID-19) and multiple disease combinations (COVID-19, RA, AS, GA), and mainly involves response to lipopolysaccharide, positive regulation of cytokine production, cytokine receptor binding.

FIGURE 3

Module function analysis of common targets of multiple disease combinations (COVID-19, RA, AS, GA). After the functional analysis of the module, the 99 targets can be aggregated into eight modules, and the circle of each color represents one module, which is mainly related to immune response, inflammatory progression, bacteria and virus expression and other functions. And there is a close relationship between the enriched targets on each module, and also has a certain correlation with the targets on other modules.

FIGURE 4

Common signaling pathways of single disease (COVID-19) and multiple disease combinations (COVID-19, RA, AS, GA). (A,B) The common signaling pathways involved in multiple disease combinations (COVID-19, RA, AS, GA) and the pathways that rank TOP20 among them. (C,D) The signaling pathways regulated by single disease (COVID-19) and the pathways of ranking TOP20. (E) Based on the intersection analysis of TOP20 pathways in single disease (COVID-19) and multiple disease combinations (COVID-19, RA, AS, GA), 12 common regulated signaling pathways were obtained, including Coronavirus disease, TNF signaling pathway, IL-17 signaling pathway, and showed the enriched targets on each pathway. (F–H) Specific signaling transduction pathways of Coronavirus disease, TNF signaling pathway and IL-17 signaling pathway.

FIGURE 5

Potential molecular mechanism of CEP in the treatment of COVID-19. (A) The molecular structure of CEP is a double segment isovaline alkaloid with a molecular formula of C₃₇H₃₈N₂O₆. (B) Which is the common targets of CEP and COVID-19. (C) Results of GO analysis shows the process of ranking TOP10, which mainly involves cell proliferation, cell biological regulation and protein transcription and translation. (D) Results of KEGG analysis mainly regulate signaling pathways such as PI3K-Akt signaling pathway, Relaxin signaling pathway, VEGF signaling pathway and HIF-1 signaling pathway. (E) CEP-action targets-signaling pathways-COVID-19 association network, purple represents the TCM component CEP, blue represents the action targets, the larger the shape, the more important the target, yellow is the signaling pathways, orange represents the disease COVID-19, showing that CEP has the characteristics of multi-targets and multi-pathways therapy. (F–I) Molecular docking result of CEP and AKT1, PIK3CA, PIK3CD, ACE2.