6-thioguanine inhibits EV71 replication by reducing BIRC3-mediated autophagy.

Background: Enterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD), and can cause severe cerebral complications and even fatality in children younger than 5 years old. However, there is no specific medication for EV71 infection in clinical practice. Our previous studies had identified the 6-thioguanine (6-TG), an FDA-approved anticancer drug, as a potential antiviral agent, but its anti-EV71 activity is largely unknown, therefore, we aim to explore the antiviral effect of 6-TG on EV71.

Results: 6-TG significantly suppressed EV71 mRNA level, VP1 protein expression, and viral progeny production in HT-29 cells. In EV71-infected HT-29 cells, the 50% cytotoxicity concentration of 6-TG (CC) was > 2000 µM and the 50% inhibitory concentration of 6-TG against EV71 (IC) was 0.9302 µM. Interestingly, the selectivity index (SI) value of 6-TG against EV71 was > 2150.1, which was higher than the SI value (> 66.7) of ribavirin. Mechanistically, 6-TG treatment reduced the expression of baculoviral IAP repeat containing 3 (BIRC3), and further inhibited EV71 replication by attenuating BIRC3-mediated the complete autophagy.

Conclusions: 6-TG exerted a significant inhibitory effect on EV71 infection in vitro and prevented EV71-induced the complete autophagy by decreasing BIRC3 expression. Our work provided a basis for the further development of 6-TG as a therapy for EV71-associated HFMD.