In silico investigations of heparin binding to SARS-CoV-2 variants with a focus at the RBD/ACE2 interface.

The increased infectivity and transmissibility of SARS-CoV-2 new variants were contributed largely by increase binding of receptor binding domain (RBD) domain of the Spike (S) protein to its cellular receptor ACE2 (Angiotensin-Converting Enzyme 2). Several studies have indicated that heparin and its derivatives interact to SARS-CoV-2 S-RBD and inhibits the binding of ACE2 which blocks the viral invasion. However, it is largely unclear how these SARS-CoV-2 variants affects ACE2 binding in the presence of heparin. Herein, using the molecular docking and interaction energy analysis, we showed that N501Y, L452R-E484Q, and E484K mutations bind strongly with heparin in the range of - 7.4 to - 8.0 kcal/mol. The triple mutations, K417N-E484K-N501Y, and K417T-E484K-N501Y displayed weaker binding affinity to heparin (-6.6 kcal/mol). Further, we showed that most of the RBD mutations increased the binding affinity of ACE2 in the absence of heparin, with the maximum increase observed for N501Y (-13.7 kcal/mol). Also, in the presence of heparin, ACE2 binds strongly to the mutant RBD as compared to WT RBD. The strong RBD/ACE2 interaction was observed in case of triple variants (-11.3 kcal/mol) whereas, N501Y showed weakest binding of RBD/ACE2 in the presence of heparin (-9.2 kcal/mol). The strong binding of ACE2 to RBD-heparin complex in these variants will leads to strong inhibition of their entry into host cells.

Insights into the SARS-CoV-2-Mediated Alteration in the Stress Granule Protein Regulatory Networks in Humans.

The rapidly and constantly evolving coronavirus, SARS-CoV-2, imposes a great threat to human health causing severe lung disease and significant mortality. Cytoplasmic stress granules (SGs) exert anti-viral activities due to their involvement in translation inhibition and innate immune signaling. SARS-CoV-2 sequesters important SG nucleator proteins and impairs SG formation, thus evading the host response for efficient viral replication. However, the significance of SGs in COVID-19 infection remains elusive. In this study, we utilize a protein-protein interaction network approach to systematically dissect the crosstalk of human post-translational regulatory networks governed by SG proteins due to SARS-CoV-2 infection. We uncovered that 116 human SG proteins directly interact with SARS-CoV-2 proteins and are involved in 430 different brain disorders including COVID-19. Further, we performed gene set enrichment analysis to identify the drugs against three important key SG proteins (DYNC1H1, DCTN1, and LMNA) and also looked for potential microRNAs (miRNAs) targeting these proteins. We identified bexarotene as a potential drug molecule and miRNAs, hsa-miR-615-3p, hsa-miR-221-3p, and hsa-miR-124-3p as potential candidates for the treatment of COVID-19 and associated manifestations.

Genomics-guided targeting of stress granule proteins G3BP1/2 to inhibit SARS-CoV-2 propagation.

SARS-CoV-2 nucleocapsid (N) protein undergoes RNA-induced phase separation (LLPS) and sequesters the host key stress granule (SG) proteins, Ras-GTPase-activating protein SH3-domain-binding protein 1 and 2 (G3BP1 and G3BP2) to inhibit SG formation. This will allow viral packaging and propagation in host cells. Based on a genomic-guided meta-analysis, here we identify upstream regulatory elements modulating the expression of G3BP1 and G3BP2 (collectively called G3BP1/2). Using this strategy, we have identified FOXA1, YY1, SYK, E2F-1, and TGFBR2 as activators and SIN3A, SRF, and AKT-1 as repressors of G3BP1/2 genes. Panels of the activators and repressors were then used to identify drugs that change their gene expression signatures. Two drugs, imatinib, and decitabine have been identified as putative modulators of G3BP1/2 genes and their regulators, suggesting their role as COVID-19 mitigation agents. Molecular docking analysis suggests that both drugs bind to G3BP1/2 with a much higher affinity than the SARS-CoV-2 N protein. This study reports imatinib and decitabine as candidate drugs against N protein and G3BP1/2 protein.

Targeting hub genes and pathways of innate immune response in COVID-19: A network biology perspective.

The current pandemic of 2019 novel coronavirus disease (COVID-19) caused by a novel virus strain, 2019-nCoV/SARS-CoV-2 have posed a serious threat to global public health and economy. It is largely unknown how the human immune system responds to this infection. A better understanding of the immune response to SARS-CoV-2 will be important to develop therapeutics against COVID-19. Here, we have used transcriptomic profile of human alveolar adenocarcinoma cells (A549) infected with SARS-CoV-2 and employed a network biology approach to generate human-virus interactome. Network topological analysis discovers 15 SARS-CoV-2 targets, which belongs to a subset of interferon (IFN) stimulated genes (ISGs). These ISGs (IFIT1, IFITM1, IRF7, ISG15, MX1, and OAS2) can be considered as potential candidates for drug targets in the treatments of COVID-19. We have identified significant interaction between ISGs and TLR3 agonists, like poly I: C, and imiquimod, and suggests that TLR3 agonists can be considered as a potential drug for drug repurposing in COVID-19. Our network centric analysis suggests that moderating the innate immune response is a valuable approach to target COVID-19.