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There is currently no approved antiviral therapy for treatment of Ebola virus disease. To discover readily available approved drugs that can be rapidly repurposed for treatment of Ebola virus infections, we screened 1280 FDA-approved drugs and identified glycopeptide antibiotic teicoplanin inhibiting Ebola pseudovirus infection by blocking virus entry in the low micromolar range. Teicoplanin could be evaluated further and incorporated into ongoing clinical studies.

There is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections, which remain a substantial threat to public health. To discover inhibitors that can be immediately repurposed for treatment of enterovirus infections, we developed a high-throughput screening assay that measures the cytopathic effect induced by enterovirus 71 (EV71) to screen an FDA-approved drug library. Itraconazole (ITZ), a triazole antifungal agent, was identified as an effective inhibitor of EV71 replication in the low-micromolar range (50% effective concentrations [EC 50 s], 1.15 M). Besides EV71, the compound also inhibited other enteroviruses, including coxsackievirus A16, coxsackievirus B3, poliovirus 1, and enterovirus 68. Study of the mechanism of action by time-of-addition assay and transient-replicon assay revealed that ITZ targeted a step involved in RNA replication or polyprotein processing. We found that the mutations (G5213U and U5286C) conferring the resistance to the compound were in nonstructural protein 3A, and we confirmed the target amino acid substitutions (3A V51L and 3A V75A) using a reverse genetic approach. Interestingly, posaconazole, a new oral azole with a molecular structure similar to that of ITZ, also exhibited anti-EV71 activity. Moreover, ITZ-resistant viruses do not exhibit cross-resistance to posaconazole or the enviroxime-like compound GW5074, which also targets the 3A region, indicating that they may target a specific site(s) in viral genome. Although the protective activity of ITZ or posaconazole (alone or in combination with other antivirals) remains to be assessed in animal models, our findings may represent an opportunity to develop therapeutic interventions for enterovirus infection.

BackgroundIn 2012 a large outbreak of hand, foot, and mouth disease (HFMD) widely spread over China, causing more than 2 million cases and 567 deaths. Our purpose was to characterize the major pathogens responsible for the 2012 HFMD outbreak and analyze the genetic characterization of the enterovirus 71 (EV71) strains in Shanghai; also, to analyze the dynamic patterns of neutralizing antibody (NAb) against EV71 and evaluate the diagnostic value of several methods for clinical detection of EV71.MethodsClinical samples including stool, serum and CSF were collected from 396 enrolled HFMD inpatients during the peak seasons in 2012. We analyzed the molecular epidemiology, clinical feature, and diagnostic tests of EV71 infection.ResultsEV71 was responsible for 60.35 % of HFMD inpatients and 88.46 % of severe cases. The circulating EV71 strains belonged to subgenogroup C4a. The nucleotide sequences of VP1 between severe cases and uncomplicated cases shared 99.2 ~ 100 % of homology. Among 218 cases with EV71 infection, 211 (96.79 %) serum samples showed NAb positive against EV71 and NAb titer reached higher level 3 days after disease onset. Of 92 cases with EV71-associated meningitis or encephalitis, 5 (5.43 %) of 92 had EV71 RNA detected in CSF samples. The blood anti-EV71 IgM assay showed a sensitivity of 93.30 % and a specificity of 50 %.ConclusionsEV71 C4a remained the predominant subgenotype circulating in Shanghai. The severity of the EV71 infection is not associated with the virulence determinants in VP1. RT-PCR together with IgM detection can enhance the early diagnosis of severe EV71-associated HFMD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-015-0308-2) contains supplementary material, which is available to authorized users.