| Summary: | 碩士 === 國立陽明大學 === 醫學生物技術暨檢驗學系 === 106 === Enterovirus 71 (EV71) mainly infects young children, causing mild hand, foot, and mouth disease and infrequently severe neurological diseases or even death. However, the treatment of EV71 infections remains an unmet medical need. As an effort to uncover EV71 replication inhibitors, we screened the BML-2843 drug library comprising 800 members of US FDA-approved drugs. The screening identified sertraline, an antidepressant of the selective serotonin uptake inhibitor class, as an anti-EV71 agent among others. Sertraline significantly inhibited viral protein expression in a dose-dependent manner, with 50% effective concentration at about 2 µM. Time-of-addition study revealed that sertraline effectively inhibited EV71 replication at the early stage (before 1 h post-adsorption). Sertraline did not appear to be virucidal, nor did it interfere with viral-binding or -internalization. Sertraline prohibited labeled-transferrin from endocytosis of host cells, suggesting that the drug might inhibit viral replication by targeting the endocytosis stage. This is supported by the finding that dynasore, a compound targeting several components in the endocytosis, also inhibited EV71 replication in a dose-dependent manner. Over- expression of endocytosis-related dynamin 2 or treatment of lipid raft-related cholesterol could not counteract the inhibitory effect of sertraline on EV71 infections, suggesting that the antiviral effect of sertraline is probably not correlated with dynamin 2 and cholesterol, both mediate the endocytosis of EV71 by host cells. Moreover, the antiviral effects extended to several other EV species independent of cytotoxicity. This new use of an antidepressant sertraline as a potent anti-EV agent with the endocytosis-targeting effect might provide novel perspectives for treating EV71 infections.
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