Abstract
Aims: Coxsackievirus B3 (CVB3) is known to be an important cause of myocarditis and dilated cardiomyopathy. Enterovirus-2C (E2C) is a viral RNA helicase. It inhibits host protein synthesis. Based on these facts, we hypothesize that the inhibition of 2C may suppress virus replication and prevent enterovirus-mediated cardiomyopathy. Methods and Results: We generated a chemically modified enterovirus-2C inhibitor (E2CI). From the in vitro assay, E2CI was showed strong antiviral effects. For in vivo testing, mice were treated with E2CI intraperitoneally injected daily for three consecutive days at a dose of 8 mg/kg per day, after CVB3 post-infection (p.i) (CVB3 + E2CI, n = 33). For the infected controls (CVB3 only, n = 35), mice were injected with PBS (phosphate buffered saline) in a DBA/2 strain to establish chronic myocarditis. The four-week survival rate of E2CI-treated mice was significantly higher than that of controls (92% vs. 71%; p < 0.05). Virus titers and myocardial damage were significantly reduced in the E2CI treated group. In addition, echocardiography indicated that E2CI administration dramatically maintained mouse heart function compared to control at day 28 p.i chronic stage (LVIDD, 3.1 ± 0.08 vs. 3.9 ± 0.09, p < 0.01; LVDS, 2.0 ± 0.07 vs. 2.5 ± 0.07, p < 0.001; FS, 34.8 ± 1.6% vs. 28.5 ± 1.5%; EF, 67. 9 ± 2.9% vs. 54.7 ± 4.7%, p < 0.05; CVB3 + E2CI, n = 6 vs. CVB3, n = 4). Moreover, E2CI is effectively worked in human iPS (induced pluripotent stem cell) derived cardiomyocytes. Conclusion: Enterovirus-2C inhibitor (E2CI) was significantly reduced viral replication, chronic myocardium damage, and CVB3-induced mortality in DBA/2 mice. These results suggested that E2CI is a novel therapeutic agent for the treatment of enterovirus-mediated diseases.
Highlights
Coxsackievirus B3 (CVB3) is identified as one of the most common etiological agents for heart diseases such as myocarditis and cardiomyopathy
We evaluated the antiviral activity of synthetic chemicals and chose enterovirus-2C inhibitor (E2CI) (CVB3 RNA helicase 2C inhibitor) as the candidate to develop an antiviral agent against CVB3-induced viral myocarditis
It is first time that CVB3 infection and antiviral effects in human cardiomyocyte were proven. These findings strongly suggest that E2CI may be developed as a new drug for cardiomyopathy associated with CVB3 infection
Summary
Coxsackievirus B3 (CVB3) is identified as one of the most common etiological agents for heart diseases such as myocarditis and cardiomyopathy It belongs to the picornavirus family and enterovirus genus. Effective vaccines and therapeutic drugs are not well-established, because RNA viruses change their capsid proteins and escape immune responses Limited treatment, such as IFN-gamma and immunoglobulin, is performed. We evaluated the antiviral activity of synthetic chemicals and chose E2CI (CVB3 RNA helicase 2C inhibitor) as the candidate to develop an antiviral agent against CVB3-induced viral myocarditis. E2CI significantly inhibited the replication of CVB3 and reduced heart damage and inflammations It preserved left-ventricular (LV) function and progression to DCMP in a murine viral myocarditis model. E2CI may be developed as a therapeutic drug for CVB3-induced myocarditis
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