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MNK1 inhibitor as an antiviral agent suppresses buffalopox virus protein synthesis

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Title MNK1 inhibitor as an antiviral agent suppresses buffalopox virus protein synthesis
Not Available
 
Creator Ram Kumara, Nitin Khandelwal, Yogesh Chander, Thachamvally Riyesh, Bhupendra N. Tripathi, Sudhir Kumar Kashyap, Sanjay Barua, Sunil Maherchandani, Naveen Kumar
 
Subject MNK1 CGP57380 Antiviral efficacy Protein synthesis Drug resistance
 
Description Not Available
A small molecule chemical inhibitor CGP57380 that blocks activation of MAPK interacting kinase 1 (MNK1) was
found to significantly suppress buffalopox virus (BPXV) replication. BPXV infection was shown to induce MNK1
activation. Depletion of MNK1 by small interfering RNA (siRNA), blocking activation of extracellular regulated
kinase (ERK, an upstream activator of MNK1) and disruption of eIF4E/eIF4G interaction (downstream substrate
of MNK1 which plays a central role in cap-dependent translation initiation), resulted in reduced BPXV replication,
suggesting that ERK/MNK1/eIF4E signaling is a prerequisite for BPXV replication. With the help of
time-of-addition and virus step-specific assays, CGP57380 treatment was shown to decrease synthesis of viral
genome (DNA). Disruption of ERK/MNK1/eIF4E signaling resulted in reduced synthesis of viral proteins, suggesting
that BPXV utilizes cap-dependent mechanism of translation initiation. Therefore, we concluded that
decreased synthesis of viral genome in presence of MNK1 inhibitor is the result of reduced synthesis of viral
proteins. Furthermore, BPXV was sequentially passaged (P=40) in presence of CGP57380 or vehicle control
(DMSO). As compared to P0 and P40-control viruses, P40-CGP57380 virus replicated at significantly higher
(∼10-fold) titers in presence of CGP57380, although a complete resistance could not be achieved. In a BPXV egg
infection model, CGP57380 was found to prevent development of pock lesions on chorioallantoic membrane
(CAM) as well as associated mortality of the embryonated chicken eggs. We for the first time demonstrated in
vitro and in ovo antiviral efficacy of CGP57380 against BPXV and identified that ERK/MNK1 signaling is a
prerequisite for synthesis of viral proteins. Our study also describes a rare report about generation of drugresistant
viral variants against a host-targeting antiviral agent.
Not Available
 
Date 2018-12-01T07:12:50Z
2018-12-01T07:12:50Z
2018-11-01
 
Type Article
 
Identifier https://doi.org/10.1016/j.antiviral.2018.10.022
Not Available
http://krishi.icar.gov.in/jspui/handle/123456789/14815
 
Language English
 
Relation Not Available;
 
Publisher Elsevier