Bioinformatic Approaches for Identification of Potential Repurposable Drugs in COVID-19
Introduction: Repurposing existing drugs approved for other conditions is crucial to identifying specific therapeutics against SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) causing COVID-19 (coronavirus disease 2019) pandemic. Towards this attempt, it is important to understand how this virus hijacks the host system during the course of infection and determine potential virus- and host-targeted inhibitors.
Methods: This study elucidates the underlying virus-host interaction based on differentially expressed gene profiling, functional enrichment and pathway analysis, protein-protein and protein-drug interactions utilizing the information on transcriptional response to SARS-CoV-2 infection from GSE147507 dataset containing COVID-19 case relative to healthy control and infected cell culture compared to uninfected one.
Results: Low IFN signaling, chemokines level elevation, and proinflammatory cytokines release were observed markedly. We identified MYC-rapamycin and ABCG2-rapamycin interactions, and unique gene signatures in case (regulation of protein modification and MAPK signaling) as well as in cell (metabolic dysregulation and interferon signaling) different from known COVID-19 genes.
Conclusion: Among a plethora of repurposable drugs those appearing here with unique gene signatures might be helpful in COVID-19
Keywords: COVID-19, SARS-CoV-2, GSE 147507 dataset, protein-protein interaction, gene-drug interaction, repurposable drugs.
2. Shaha B, Modia P, Sagara SR. In silico studies on therapeutic agents for COVID-19: drug repurposing approach. Life Sci 2020; 252:117652.
3. Gordon DE, Jang GM, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020. doi: 10.1038/s41586-020-2286-9
4. Guy RK, DiPaola RS, Romanelli F, et al. Rapid repurposing of drugs for COVID-19. Science 2020; 368: 829-30.
5. Shahreza ML, Ghadiri N, Mousavi SR, et al. A review of network-based approaches to drug repositioning. Brief Bioinform 2018; 19:878-92.
6. Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced host response to SARS-CoV-2 drives development of COVID-19. Cell 2020; 181:1036-45.
7. Doncheva NT, Morris JH, Gorodkin JL. Cytoscape stringapp: network analysis and visualization of proteomics data. J Proteome Res 2019; 18:623-32.
8. Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498-2504.
9. Huber W, Carey VJ, Gentleman R, et al. Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods 2015; 12:115-21.
10. Li G, Clercq DE, Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov 2020; 19: 149-50.
11. de Wilde AH, Snijder EJ, Kikkert M, et al. Host factors in coronavirus replication. Curr Topics Microbiol Immunol 2018; 419:1-42.
12. Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. PNAS 2020; 117:11727-34.
13. Kim D, Lee JY, Yang JS, et al. The architecture of SARS-CoV-2 transcriptome. Cell 2020; 181:914-21.
14. Wathelet MG, Orr M, Frieman MB, et al. Severe acute respiratory syndrome coronavirus evades antiviral signaling: role of nsp1 and rational design of an attenuated strain. J Virol 2007; 81:11620-33.
15. WikiPathways Portal: disease/COVID pathways (June 22, 2020), https://www.wikipathways.org/index.php/Portal:Disease/COVIDPathways (accessed 22.06.2020).
16. Deng X, Hackbart M, Mettelman RC, et al. Coronavirus nsp15 mediates evasion of dsRNA sensors and limits apoptosis in macrophages. PNAS 2017; 114:E4251-E4260.
17. Surjit M, Liu B, Chow VT, et al. The nucleocapsid protein of severe acute respiratory syndrome-coronavirus inhibits the activity of cyclin-cyclin-dependent kinase complex and blocks S phase progression in mammalian cells. J Biol Chem 2006; 281:10669-81.
18. Wu CH, Chen PJ, Yeh SH. Nucleocapsid phosphorylation and RNA helicase DDX1 recruitment enables coronavirus transition from discontinuous to continuous transcription. Cell Host Microbe 2014; 16:462-72.
19. Liao Y, Wang X, Huang M, et al. Regulation of the p38 mitogen-activated protein kinase and dual-specificity phosphatase 1 feedback loop modulates the induction of interleukin 6 and 8 in cells infected with coronavirus infectious bronchitis virus. Virology 2011; 420:106-16.
20. Josh RJ, Manuel A. COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med 2020; 8:E46-7.
21. Schoggins JM, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opinion Virol 2011; 1:519-25.
22. Mick E, Kamm J, Pisco AO, et al. Upper airway gene expression differentiates COVID-19 from other acute respiratory illnesses and reveals suppression of innate immune responses by SARS-CoV-2. medRxiv 2020. doi:10.1101/2020.05.18.20105171
23. GeneCards, The human gene database, https://www.genecards.org/ (accessed 22.06.2020).
24. Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases? Nat Rev.Immunol 2020; 20:271-2.
25. Ouyang Y, Yin J, Wang W, et al. Down-regulated gene expression spectrum and immune responses changed during the disease progression in COVID-19 patients. Clin Infect Dis 2020; ciaa462. doi: 10.1093/cid/ciaa462
26. Feng Y, Ni L, Wan H, et al. Overexpression of ACE2 produces antitumor effects via inhibition of angiogenesis and tumor cell invasion in vivo and in vitro. Oncol Rep 2011; 26:1157-64.
27. Kumari N, Dwarakanath BS, Das A, et al. Role of interleukin-6 in cancer progression and therapeutic resistance. Tumor Biol 2016; 37:11553-72.
28. Khalil RA, Morgan KG. Enzyme translocations during smooth muscle activation, In Biochemistry of Smooth Muscle Contraction 1996; 307-318.
29. Vara JAE, Casado Castro EJ, et al. PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 2004; 30:193-204.
30. Human Protein Atlas (Version 9.3., 2020), https://www.proteinatlas.org/ (accessed 22.06. 2020).
31. Ciliberto G, Mancini R, Paggi MG. Drug repurposing against COVID-19: focus on anticancer agents. J Exp Clin Canc Res 2020; 39:86.
32. Bellingan G, Maksimow M, Howell DC, et al. The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study. Lancet Respir Med 2014; 2: 98–107.
33. Caly L, Druce JD, Catton M, et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res 2020; 178:104787.
34. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020: 382: 2327-36.
35. Wu R, Wang L, Kuo HCD, et al. An update on current therapeutic drugs treating COVID-19. Curr Pharmacol Rep 2020; 6:56–70.
36. Uno Y. Camostat mesilate therapy for COVID 19. Intern Emerg. Med 2020; doi: 10.1007/s11739-020-02345-9
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