1. Genomics-guided targeting of stress granule proteins G3BP1/2 to inhibit SARS-CoV-2 propagation.
- Author
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Ali N, Prasad K, AlAsmari AF, Alharbi M, Rashid S, and Kumar V
- Subjects
- Adaptor Proteins, Signal Transducing antagonists & inhibitors, Adaptor Proteins, Signal Transducing metabolism, COVID-19 metabolism, Coronavirus Nucleocapsid Proteins metabolism, DNA Helicases antagonists & inhibitors, DNA Helicases metabolism, Decitabine pharmacology, Drug Delivery Systems, Genomics, Imatinib Mesylate pharmacology, Phosphoproteins chemistry, Phosphoproteins metabolism, Poly-ADP-Ribose Binding Proteins antagonists & inhibitors, Poly-ADP-Ribose Binding Proteins metabolism, RNA Helicases antagonists & inhibitors, RNA Helicases metabolism, RNA Recognition Motif Proteins antagonists & inhibitors, RNA Recognition Motif Proteins metabolism, RNA-Binding Proteins antagonists & inhibitors, RNA-Binding Proteins metabolism, SARS-CoV-2 metabolism, Adaptor Proteins, Signal Transducing chemistry, Coronavirus Nucleocapsid Proteins chemistry, DNA Helicases chemistry, Decitabine chemistry, Imatinib Mesylate chemistry, Molecular Docking Simulation, Molecular Dynamics Simulation, Poly-ADP-Ribose Binding Proteins chemistry, RNA Helicases chemistry, RNA Recognition Motif Proteins chemistry, RNA-Binding Proteins chemistry, SARS-CoV-2 chemistry, COVID-19 Drug Treatment
- Abstract
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., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
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