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Targeting host protein G3BP1 for the discovery of novel antiviral inhibitors against the Chikungunya virus
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Targeting host protein G3BP1 for the discovery of novel antiviral inhibitors against the Chikungunya virus
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Targeting host protein G3BP1 for the discovery of novel antiviral inhibitors against the Chikungunya virus
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Paper
Targeting host protein G3BP1 for the discovery of novel antiviral inhibitors against the Chikungunya virus
2022,2024
Overview
Molecular interactions of Chikungunya virus (CHIKV) non-structural protein 3 (nsP3) with GTPase Activating Protein SH3 Domain Binding Protein 1 (G3BP1) host protein is important for efficient replication of CHIKV. CHIKV nsP3 protein binds to the nuclear transport factor 2 (NTF2)-like domain of G3BP1 via two tandem FGDF motifs and disrupts the stress granules (SGs) formation. Interestingly, this makes the G3BP1 host protein an additional drug target for antiviral research. In this study, seven potential small molecules targeting FGDF motif binding pocket of G3BP1 have been identified using structure-based virtual screening approach. Binding energies and binding modes of the molecules were further analyzed in detail through molecular docking, dynamics and simulations. Surface Plasmon Resonance (SPR) and Isothermal Titration Calorimetry (ITC) experiments confirmed the binding of identified molecules to purified G3BP1 with binding affinities in micromolar (μM) range. The antiviral efficacy of molecules targeting G3BP1 was evaluated by in vitro cell culture-based antiviral studies. All seven molecules L-7, WIN, SB2, NAL, DHD, GSK and FLU effectively diminished the CHIKV replication with EC50 values of 1.996, 0.403, 5.387, 1.528, 7.394, 3.664, and 0.618 μM, respectively. Moreover, the CHIKV infected cells treated with these molecules seemed to have fewer virus-induced SGs than virus infected control cells. Interestingly, the inhibitors showed no adverse effect on SG formation in oxidative stress condition. It further substantiated that these inhibitors effectively bind to the NTF2-like domain of G3BP1, obstruct the nsP3-G3BP1 interactions, and halts virus replication. This is the first report of small molecules targeting G3BP1, the host protein playing a crucial role in CHIKV viral replication and in the formation of SGs for host antiviral response.Competing Interest StatementThe authors have declared no competing interest.
Publisher
Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
Subject
