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Deciphering Molecular Mechanisms of Sars-Cov-2 Pathogenesis and Drug Repurposing Through Grn Motifs: A Comprehensive Systems Biology Study Publisher



Sameni M1, 2 ; Mirmotalebisohi SA1, 2 ; Dehghan Z4 ; Abooshahab R3 ; Khazaeipoul Y1, 2 ; Mozafar M5 ; Zali H6, 7
Authors
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Authors Affiliations
  1. 1. Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  2. 2. Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  3. 3. Curtin Medical School, Curtin University, Bentley, 6102, WA, Australia
  4. 4. Department of Comparative Biomedical Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
  5. 5. Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Tehran University of Medical Science, Tehran, Iran
  6. 6. Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran, Iran
  7. 7. Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Source: 3 Biotech Published:2023


Abstract

The world has recently been plagued by a new coronavirus infection called SARS-CoV-2. This virus may lead to severe acute respiratory syndrome followed by multiple organ failure. SARS-CoV-2 has approximately 80–90% genetic similarity to SARS-CoV. Given the limited omics data available for host response to the viruses (more limited data for SARS-CoV-2), we attempted to unveil the crucial molecular mechanisms underlying the SARS-CoV-2 pathogenesis by comparing its regulatory network motifs with SARS-CoV. We also attempted to identify the non-shared crucial molecules and their functions to predict the specific mechanisms for each infection and the processes responsible for their different manifestations. Deciphering the crucial shared and non-shared mechanisms at the molecular level and signaling pathways underlying both diseases may help shed light on their pathogenesis and pave the way for other new drug repurposing against COVID-19. We constructed the GRNs for host response to SARS-CoV and SARS-CoV-2 pathogens (in vitro) and identified the significant 3-node regulatory motifs by analyzing them topologically and functionally. We attempted to identify the shared and non-shared regulatory elements and signaling pathways between their host responses. Interestingly, our findings indicated that NFKB1, JUN, STAT1, FOS, KLF4, and EGR1 were the critical shared TFs between motif-related subnetworks in both SARS and COVID-1, which are considered genes with specific functions in the immune response. Enrichment analysis revealed that the NOD-like receptor signaling, TNF signaling, and influenza A pathway were among the first significant pathways shared between SARS and COVID-19 up-regulated DEGs networks, and the term “metabolic pathways” (hsa01100) among the down-regulated DEGs networks. WEE1, PMAIP1, and TSC22D2 were identified as the top three hubs specific to SARS. However, MYPN, SPRY4, andAPOL6 were the tops specific to COVID-19 in vitro. The term “Complement and coagulation cascades” pathway was identified as the first top non-shared pathway for COVID-19 and the MAPK signaling pathway for SARS. We used the identified crucial DEGs to construct a drug–gene interaction network to propose some drug candidates. Zinc chloride, Fostamatinib, Copper, Tirofiban, Tretinoin, and Levocarnitine were the six drugs with higher scores in our drug–gene network analysis. © 2023, King Abdulaziz City for Science and Technology.
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