Disruption of Molecular Interactions between the G3BP1 Stress Granule Host Protein and the Nucleocapsid (NTD-N) Protein Impedes SARS-CoV-2 Virus Replication.

Disruption of Molecular Interactions between the G3BP1 Stress Granule Host Protein and the Nucleocapsid (NTD-N) Protein Impedes SARS-CoV-2 Virus Replication.

Publication date: Dec 21, 2024

The Ras GTPase-activating protein SH3-domain-binding protein 1 (G3BP1) serves as a formidable barrier to viral replication by generating stress granules (SGs) in response to viral infections. Interestingly, viruses, including SARS-CoV-2, have evolved defensive mechanisms to hijack SG proteins like G3BP1 for the dissipation of SGs that lead to the evasion of the host’s immune responses. Previous research has demonstrated that the interaction between the NTF2-like domain of G3BP1 (G3BP1) and the intrinsically disordered N-terminal domain (NTD-N) of the N-protein plays a crucial role in regulating viral replication and pathogenicity. Interestingly, the current study identified an additional upstream stretch of residues (128KDGIIWVATEG138) (N) within the N-terminal domain of the N-protein (NTD-N) that also forms molecular contacts with the G3BP1 protein, as revealed through in silico analysis, site-directed mutagenesis, and biochemical analysis. Remarkably, WIN-62577, and fluspirilene, the small molecules targeting the conserved peptide-binding pocket in G3BP1, not only disrupted the protein-protein interactions (PPIs) between NTD-N and G3BP1 but also exhibited significant antiviral efficacy against SARS-CoV-2 replication with EC values of ∼1. 8 and ∼1. 3 μM, respectively. The findings of this study, validated by biophysical thermodynamics and biochemical investigations, advance the potential of developing therapeutics targeting the SG host protein against SARS-CoV-2, which may also serve as a broad-spectrum antiviral target.

Concepts Keywords
128kdgiiwvateg138 Binding
Biochemistry Cov
Pathogenicity Domain
Thermodynamics G3bp1
Viral Host
Interactions
Molecular
Ntd
Protein
Replication
Sars
Sgs
Stress
Viral

Semantics

Type Source Name
disease IDO host
disease IDO protein
disease IDO replication
drug DRUGBANK Rasagiline
pathway KEGG Viral replication
disease MESH viral infections
disease IDO role
disease IDO site
drug DRUGBANK Fluspirilene

Original Article

(Visited 1 times, 1 visits today)