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

Nemat Ali; Kartikay Prasad; Abdullah F AlAsmari; Metab Alharbi; Summya Rashid; Vijay Kumar

doi:10.1016/j.ijbiomac.2021.09.018

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

Int J Biol Macromol. 2021 Nov 1:190:636-648. doi: 10.1016/j.ijbiomac.2021.09.018. Epub 2021 Sep 10.

Authors

Nemat Ali¹, Kartikay Prasad², Abdullah F AlAsmari¹, Metab Alharbi¹, Summya Rashid³, Vijay Kumar⁴

Affiliations

¹ Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
² Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, UP 201303, India.
³ Department of Pharmacology & Toxicology, College of Pharmacy Girls Section, Prince Sattam Bin AbdulAziz University, Al kharj 11942, Saudi Arabia.
⁴ Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, UP 201303, India. Electronic address: vkumar33@amity.edu.

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.

Keywords: Decitabine; G3BP1/2; Gene set enrichment; Imatinib; Nucleocapsid protein; SARS-CoV-2; Stress granule.

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors
Adaptor Proteins, Signal Transducing / chemistry*
Adaptor Proteins, Signal Transducing / metabolism
COVID-19 / metabolism
COVID-19 Drug Treatment*
Coronavirus Nucleocapsid Proteins / chemistry*
Coronavirus Nucleocapsid Proteins / metabolism
DNA Helicases / antagonists & inhibitors
DNA Helicases / chemistry*
DNA Helicases / metabolism
Decitabine / chemistry*
Decitabine / pharmacology
Drug Delivery Systems
Genomics
Imatinib Mesylate / chemistry*
Imatinib Mesylate / pharmacology
Molecular Docking Simulation*
Molecular Dynamics Simulation*
Phosphoproteins / chemistry
Phosphoproteins / metabolism
Poly-ADP-Ribose Binding Proteins / antagonists & inhibitors
Poly-ADP-Ribose Binding Proteins / chemistry*
Poly-ADP-Ribose Binding Proteins / metabolism
RNA Helicases / antagonists & inhibitors
RNA Helicases / chemistry*
RNA Helicases / metabolism
RNA Recognition Motif Proteins / antagonists & inhibitors
RNA Recognition Motif Proteins / chemistry*
RNA Recognition Motif Proteins / metabolism
RNA-Binding Proteins / antagonists & inhibitors
RNA-Binding Proteins / chemistry*
RNA-Binding Proteins / metabolism
SARS-CoV-2 / chemistry*
SARS-CoV-2 / metabolism

Substances

Adaptor Proteins, Signal Transducing
Coronavirus Nucleocapsid Proteins
G3BP2 protein, human
Phosphoproteins
Poly-ADP-Ribose Binding Proteins
RNA Recognition Motif Proteins
RNA-Binding Proteins
nucleocapsid phosphoprotein, SARS-CoV-2
Decitabine
Imatinib Mesylate
DNA Helicases
G3BP1 protein, human
RNA Helicases