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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.
Insights
Abietic acid (AA) effectively inhibits Coxsackievirus B3 (CVB3) replication by targeting the host protein RAN. This antiviral strategy shows promise for treating viral myocarditis (VMC) and related heart conditions.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Coxsackievirus B3 (CVB3) is a primary cause of viral myocarditis (VMC), often leading to severe heart damage and heart failure.
- Current clinical treatments for CVB3-induced VMC are limited, necessitating the development of novel therapeutic agents.
Purpose of the Study:
- To investigate the antiviral activity of abietic acid (AA) against CVB3 infection.
- To elucidate the mechanism of action of AA in inhibiting CVB3 replication.
- To evaluate the therapeutic potential of AA in a preclinical model of viral myocarditis.
Main Methods:
- In vitro antiviral assays were performed to determine the efficacy and safety of AA against CVB3 using HeLa cells.
- Mechanistic studies identified Ras-related nuclear protein (RAN) as a host dependency factor for CVB3 replication.
- In vivo studies utilized a murine model of CVB3-induced myocarditis to assess the therapeutic effects of AA.
Main Results:
- Abietic acid demonstrated potent anti-CVB3 activity (EC50 = 12.16 μM) with good biosafety (SI = 26.90).
- AA treatment significantly reduced RAN expression, restored nuclear translocation of p-STAT1/2, and enhanced interferon-stimulated gene responses.
- In vivo, AA treatment improved survival rates, reduced viral load and inflammation in cardiac tissues, and mitigated myocardial injury.
Conclusions:
- Ras-related nuclear protein (RAN) is identified as a novel antiviral target essential for CVB3 replication.
- Abietic acid inhibits CVB3 infection through the RAN-p-STAT1/2 signaling pathway.
- Abietic acid shows significant potential as a therapeutic agent for CVB3-associated viral myocarditis and other cardiovascular diseases.
Abstract:
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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