Targeting the host protein G3BP1 for the discovery of novel antiviral inhibitors against Chikungunya virus

Abstract

Molecular interactions of Chikungunya virus (CHIKV) nsP3 with the host G3BP1 stress granule (SG) protein is crucial for CHIKV replication. NsP3 binds to the nuclear transport factor 2 (NTF2)-like domain of G3BP1 via its two FGDF motifs, unsettling SGs formation. The present study identified seven small molecules targeting the FGDF binding pocket of G3BP1 using structure-based computer-aided drug discovery. All seven molecules exhibited good binding affinities in the range of [~]3.4 to [~]98M towards NTF2-like G3BP1 domain. Furthermore, identified molecules demonstrate dose-dependent inhibition in CHIKV infected Vero cells (EC50: 0.40 to 7.39{micro}M), and reduced SGs formation in these cells. These results highlight G3BP1 protein as a potential CHIKV therapeutic target and offer potential prospective for developing treatment for CHIKV disease.