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Use of Viral Entry Assays and Molecular Docking Analysis for the Identification of Antiviral Candidates against Coxsackievirus A16
Published on: July 15, 2019
Abietic acid targets RAN to restrict coxsackievirus B3 infection
Junbo Huang1, Qing Song1, Yanjun Di1
1School of Medicine, Huaqiao University, Quanzhou, China.
None:
Coxsackievirus B3 (CVB3) represents a major etiological factor of viral myocarditis (VMC). It frequently results in the damage of the heart and even heart failure, but there are few effective treatment measures that can be used clinically. In this paper, we show that abietic acid (AA), a tricyclic diterpenoid compound, has strong anti-CVB3 activity both in vitro and in vivo. AA was found to inhibit CVB3 replication with 50% effective concentration (EC50) of 12.16 μM and high selectivity index (SI = 26.90) and 50 percent cytotoxic concentration (CC50) of 327.14 μM in HeLa cells, suggesting good biosafety. Mechanistically, RAN (Ras-related nuclear protein) a central mediator of nucleocytoplasmic transport was determined to be an essential host dependency factor in CVB3 replication. The AA therapy led to a significant decrease in RAN expression, thus recovering nuclear translocation of phosphorylated STAT1/2 (p-STAT1/2) compromised by CVB3 infection, which subsequently boosts the response of interferon-stimulated genes (ISGs) downstream. AA treatment in a CVB3-induced model of murine myocarditis showed a significant increase in survival rates, lower viral loads and inflammatory cytokines in cardiac tissues, and lessened myocardial injury. Collectively, these results identify RAN as a novel antiviral target, and show that AA inhibits CVB3 infection via the RAN-p-STAT1/2 axis, supporting its potential as a promising therapeutic agent for CVB3-associated diseases.
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