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.
Subject(s)
Adaptor Proteins, Signal Transducing/chemistry , COVID-19 Drug Treatment , 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 , 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/metabolismABSTRACT
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell after the receptor binding domain (RBD) of the virus spike (S) glycoprotein binds to the human angiotensin-converting enzyme 2 (hACE2). This binding requires the RBD to undergo a conformational change from a closed to an open state. In the present study, a key pair of salt bridges formed by the side chains of K537 and E619, residues at the interfaces of SD1 and SD2, respectively, was identified to promote the opening of the RBD. Mutations of K537Q and E619D reduced their side chain lengths and eliminated this pair of salt bridges; as a result, the opening of the RBD was not observed in the MD simulations. Thus, blocking the formation of this pair of salt bridges is a promising approach for treating novel coronavirus disease 2019 (COVID-19). FDA approved drug molecules were screened by their capabilities of blocking the formation of the key pair of salt bridges, achieved by their positional stabilities in the cavity containing the side chains of K537 and E619 formed in the interface between SD1 and SD2. Simeprevir, imatinib, and naldemedine were identified to possess the desired capability with the most favorable interaction energies.