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bioRxiv · 10.1101/2022.11.11.516135

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

Mahajan, S.·Kumar, R.·Singh, A.·Pareek, A.·Long, S.·McInerney, G. M.·Tomar, S.
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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.

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Mahajan, S., Kumar, R., Singh, A., Pareek, A., Long, S., McInerney, G. M., Tomar, S.. 2022-11-11. Targeting host protein G3BP1 for the discovery of novel antiviral inhibitors against the Chikungunya virus. https://doi.org/10.1101/2022.11.11.516135

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