Antiviral activity of micafungin against enterovirus 71
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RESEARCH
Open Access
Antiviral activity of micafungin against enterovirus 71 Chonsaeng Kim3†, Hyunju Kang1,5†, Dong-eun Kim1,5†, Jae-Hyoung Song4, Miri Choi1, Mingu Kang1, Kyungjin Lee3, Hae Soo Kim3, Jin Soo Shin3, Hyejeong Jeong1, Sunhee Jung1, Sang-Bae Han5, Jong Heon Kim6, Hyun-Jeong Ko4, Chong-Kyo Lee3, Meehyein Kim3 and Sungchan Cho1,2*
Abstract Background: Enterovirus 71 (EV71) is a major causative agent of hand-foot-mouth disease (HFMD) and also causes severe neurological complications, leading to fatality in young children. However, no effective therapy is currently available for the treatment of this infection. Methods: We identified small-molecule inhibitors of EV71 from a screen of 968 Food and Drug Administration (FDA)-approved drugs, with which clinical application for EV71-associated diseases would be more feasible, using EV71 subgenomic replicon system. Primary hits were extensively evaluated for their antiviral activities in EV71-infected cells. Results: We identified micafungin, an echinocandin antifungal drug, as a novel inhibitor of EV71. Micafungin potently inhibits the proliferation of EV71 as well as the replication of EV71 replicon in cells with a low micromolar IC50 (~5 μM). The strong antiviral effect of micafungin on EV71 replicon and the result from time-of-addition experiment demonstrated a targeting of micafungin on virion-independent intracellular process(es) during EV71 infection. Moreover, an extensive analysis excluded the involvement of 2C and 3A proteins, IRES-dependent translation, and also that of polyprotein processing in the antiviral effect of micafungin. Conclusions: Our research revealed a new indication of micafungin as an effective inhibitor of EV71, which is the first case reporting antiviral activity of micafungin, an antifungal drug. Keywords: Enterovirus, Enterovirus 71 (EV71), Micafungin, FDA-approved drug, Antiviral drug
Background Enterovirus 71 (EV71) is one of the major etiological agent of hand-foot-mouth disease and also causes severe neurological symptoms, such as aseptic meningitis, encephalitis and acute flaccid paralysis, which can lead to even death [1–4]. Since its first discovery in 1969, EV71 outbreak has occurred frequently in the Asia-Pacific region and caused hundreds of annual deaths. Despite its enormous threat to public health, currently no effective vaccines or therapeutic drugs are yet available.
* Correspondence: [email protected] † Equal contributors 1 Anticancer Agent Research Center, Korea Research Institute of Bioscience & Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do 28116, South Korea 2 Department of Biomolecular Science, Korea University of Science and Technology, 217 Gajeong-ro, Daejeon 34113, South Korea Full list of author information is available at the end of the article
EV71 is a member of human enterovirus A (HEV-A) species under genus Enterovirus in the Picornaviridae family [5]. EV71 is a small and non-enveloped virus with a positive-sense single-stranded RNA genome of 7500–
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