Substituted 3-benzylcoumarins 13 and 14 suppress enterovirus A71 replication by impairing viral 2Apro dependent IRES-driven translation

Activation of the ERK signaling cascade in host cells has been demonstrated to be essential for enterovirus A71 (EV-A71) replication. Our previous study showed that MEK kinase, which specially activated downstream ERK kinase, is an important and potential target against EV-A71. Furthermore, we reported that a series of substituted 3-benzylcoumarins designed and synthesized as well as verified for inhibiting the MEK-ERK cascade were found to be effective on anti-EV-A71. In this study, we further demonstrated that two substituted 3-benzylcoumarins designated as 13 and 14 were more effective anti-MEK/ERK activity, less cytotoxicity and stronger antiviral effect represented by inhibition of viral-induced CPE, the expression of viral proteins and the replication of the viral genome, as well as the production of progeny virions, compared to those of U0126, an available MEK inhibitor, and sorafenib, a multiple-targeted kinase inhibitor in clinical use. Moreover, we explored that the likely mechanism of action of these two test compounds were to block EV-A71 2A dependent IRES-driven activity essential for successful viral replication. Hence, our results suggest that two substituted 3-benzylcoumarins 13 and 14 could be candidates as potential anti-EV-A71 agents.