Abstract

Myocarditis, the inflammatory disease of the myocardium, is one of the leading causes of dilated cardiomyopathy and sudden cardiac death. Coxsackievirus B (CVB) is one of the common pathogens of myocarditis and cardiomyopathy. In spite of the high prevalence of CVB infection, effective antiviral therapy is lacking, primarily due to that there is no approved antiviral drug available. In the previous study, we demonstrated that the neddylation of 3Dpol, the RNA-dependent RNA polymerase, promotes CVB replication. Therefore, we propose that targeting neddylation might be a therapeutic strategy for CVB infection. Here we studied the antiviral effect of MLN4924, the selective inhibitor of neddylation. We show that MLN4924 exerted potent antiviral effect with negligible cytotoxicity when applied at the early stage of CVB3 infection. MLN4924 treatment significantly inhibited viral replication both in vitro and in the myocardium of CVB3-infected mice. The myocardial damage and inflammatory response induced by CVB3 were significantly alleviated. We show that MLN4924 suppressed the neddylation of 3Dpol, leading to its upregulated degradation. Moreover, MLN4924 upregulated nuclear factor erythroid 2-related factor 2 (NRF2) through inhibiting its ubiquitination and proteasomal degradation, while CVB3 infection clearly enhanced NRF2 ubiquitination. Taken together, we conclude that MLN4924 exerts anti-CVB effect both in vitro and in vivo. In addition to inhibiting the neddylation of viral 3Dpol, upregulated NRF2 also contributes to the antiviral activity of MLN4924. This study demonstrated that targeting neddylation can be a potential antiviral strategy for the treatment of CVB infection.