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Identification of JEV capsid interacting domain(s) with host protein(s): Novel target for developing anti-JEV
Km Archana1, Ashish Agrahari1, Shriyanshi Mishra1
1Division of Virus Research and Therapeutics, CSIR- Central Drug Research Institute, Lucknow, 226031, UP, India; Academy of Scientific & Innovative Research (AcSIR) Ghaziabad, Uttar Pradesh, 201002, India.
Abstract:
The Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus. There are no approved drugs for the treatment of JEV infection.
Aim:
The virus-host protein interactions are essential for viral replication and could be novel drug targets. The JEV capsid protein does not have enzymatic functions; therefore, all functions are mediated by protein-protein interactions. We wanted to develop inhibitors to prevent such interactions.
Materials And Methods:
Our study has identified two functional domains of the capsid protein by competitive peptide binding (P2 and P7) that is crucial for JEV replication. Using pull-down and MALDI-TOF-TOF techniques, we showed that the JEV capsid protein interacts with the ANXA2 host protein via these peptide domains.
Key Findings:
In the presence of P2 and P7, ANXA-2-capsid interaction in infected cells was inhibited, and concomitantly, JEV growth was reduced in the presence of both P2 and P7. Further, we docked ~55,000 molecules from the Maybridge library and identified 10 compounds that showed favourable binding to the P7 domain. From the pool of 10 compounds, we identified SPB07257, which inhibited Capsid-ANXA2 interaction, prevented JEV infection with an IC50 of 10 μM and CC50 of ⟩50 μM.
Significance:
Our study demonstrates a novel antiviral strategy.
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