Abstract 11232: Soluble Coxsackievirus B3 3C Protease Inhibitor Prevent Enteroviral-Mediated Cardiomyopathy in Experimental Chronic Murine Myocarditis Model
Background Coxsackievirus B3 (CVB3) is known as an important cause of myocarditis and dilated cardiomyopathy in children and adult. CVB3 protease 3C (3CP) cleaves the viral polyprotein. The inhibition of 3CP can prevent CVB3-mediated myocarditis from our previous report. However, there was limitation of delivery method of 3CP inhibitor (3CPI), it is not dissolved by water, and CVB3 can induce acute cardiac damage. Methods and Results In order to address these problems, we generated water soluble 3CPI (LDD1588) by modification of 3CPI-9b chemical structure. For in vivo test, mice were treated by LDD1588 intraperitoneally injected daily for three consecutive days at a dose 50 μM per day after day3 CVB3 post-infection (p.i) (n=40) that is similar to human patient antiviral drug treatment time point. For the infected controls (n=50), mice were injected by PBS. All experiments were performed using DBA/2 strain to establish chronic myocarditis. 4-week survival rate of LDD1588-treated mice was significantly higher than that of controls (90% vs 65%; p<0.05). Virus titers and myocardial damage were significantly reduced in the LDD1588 treated group. In addition, hemodynamic measurement was indicated LDD1588 administration dramatically preserved mice heart function compare to the control mice at day21 p.i chronic stage (dP/dTmax, 5302±352 vs 4103±408, p<0.05; dP/dTmin, -3798±212 vs -2814±206 mmHg/sec, p< 0.01). In addition, echocardiography showed the strong heart protective effect of soluble 3CP inhibitor, LDD1588, at day 31 p.i. (FS, 51.2±1.5 vs 26.1±1.5 %, p<0.001; n=4 each group). Conclusion Soluble 3CPI, LDD1588, can be delivered by Intraperitoneal injection after CVB3 infection. It might inhibit activity of enterovirus 3CP, significantly reduced viral proliferation, chronic cardiac damage, and CVB3-induced mortality in chronic myocarditis DBA/2 strain. These results suggested that LDD1588 is a novel therapeutic agent for treatment of viral myocarditis.
- © 2012 by American Heart Association, Inc.