Harmine, a small molecule derived from natural sources, inhibits enterovirus 71 replication by targeting NF-kappa B pathway

Enterovirus 71 (EV71) infection of young children can cause neurological manifestations, which is mainly responsible for the fatality. Although a vaccine is recently available for preventing enterovirus 71 infection, its efficacy remains to be seen. Therefore, there is a pressing need for anti-viral agents for the treatment of EV71 infection. By screening a natural compound library for inhibitory activity of EV71 replication, we identified a small molecule, harmine, that inhibited EV71 replication by targeting NF-kappa B signaling pathway. Harmine is a beta-carboline alkaloid found in the medicinal plant Peganum harmala, which is used as a folk antitumor medicine in China and other parts of the Asia. The estimated EC50 value for harmine to block EV71 infection was 20 mu M, while the CC50 was estimated at 500 mu M in vitro. Harmine inhibited replication of EV71, as evidenced by its ability to diminish plague formation induced by EV71 and to reduce the level of viral RNA and protein. Mechanistic studies indicated that harmine suppressed EV71 replication through inhibition of NF-kappa B signaling pathway. Harmine treatment also reduced EV71-induced reactive oxygen species (ROS) formation, which was associated with a decline in EV71-associated NF-kappa B activation. In addition, the harmine treatment could protect AG129 mice against EV71 replication in vivo. These findings suggest that harmine may present as a candidate antiviral chug for the treatment of EV71 infection.