title: Synergistic antiviral activity of gemcitabine and ribavirin against enteroviruses.
abstract: Enteroviruses are major causative agents of various human diseases, and some of them are currently considered to be an enormous threat to public health. However, no effective therapy is currently available for the treatment of these infections. We identified gemcitabine, a nucleoside-analog drug used for cancer treatment, from a screen of bioactive chemicals as a novel inhibitor of coxsackievirus B3 (CVB3) and enterovirus 71 (EV71). Gemcitabine potently inhibited the proliferation of CVB3 and EV71, as well as the replication of CVB3 and EV71 replicons, in cells with a low micromolar IC50 (1-5 μM). Its strong inhibitory effect was also observed in cells infected with human rhinoviruses, demonstrating broad-spectrum antiviral effects on enteroviruses. Mechanistically, an extensive analysis excluded the involvement of 2C, 3A, IRES-dependent translation, and also that of polyprotein processing in the antiviral effects of gemcitabine. Importantly, gemcitabine in combination with ribavirin, an antiviral drug currently being used against a few RNA viruses, exhibited a synergistic antiviral effect on the replication of CVB3 and EV71 replicons. Consequently, our results clearly demonstrate a new indication for gemcitabine as an effective broad-spectrum inhibitor of enteroviruses and strongly suggest a new therapeutic strategy using gemcitabine alone or in combination with ribavirin for the treatment of various diseases associated with enterovirus infection.
authors.affiliation: Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, South Korea; College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Kang
authors.affiliation: Virus Research and Testing Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors.forename: Chonsaeng
authors.initials: C
authors.lastname: Kim
authors.affiliation: Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, South Korea; College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
authors.forename: Dong-eun
authors.initials: DE
authors.lastname: Kim
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: Jae-Hyoung
authors.initials: JH
authors.lastname: Song
authors.affiliation: Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, South Korea; College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
authors.forename: Miri
authors.initials: M
authors.lastname: Choi
authors.affiliation: Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, South Korea; Department of Medical Science, Soonchunhyang University, Asan, South Korea.
authors.forename: Kwangman
authors.initials: K
authors.lastname: Choi
authors.affiliation: Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, South Korea.
authors.forename: Mingu
authors.initials: M
authors.lastname: Kang
authors.affiliation: Virus Research and Testing Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Lee
authors.affiliation: Virus Research and Testing Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors.forename: Hae Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Virus Research and Testing Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors.forename: Jin Soo
authors.initials: JS
authors.lastname: Shin
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience & Biotechnology, Daejeon, South Korea.
authors.forename: Janghwan
authors.initials: J
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.affiliation: Department of Medical Science, Soonchunhyang University, Asan, South Korea.
authors.forename: Mi-Young
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Natural Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, South Korea.
authors.forename: Su Ui
authors.initials: SU
authors.lastname: Lee
authors.affiliation: Virus Research and Testing Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors.forename: Chong-Kyo
authors.initials: CK
authors.lastname: Lee
authors.affiliation: Virus Research and Testing Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea.
authors.forename: Meehyein
authors.initials: M
authors.lastname: Kim
authors.affiliation: Laboratory of Microbiology and Immunology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Ko
authors.affiliation: Section of Virology, Department Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
authors.forename: Frank J M
authors.initials: FJ
authors.lastname: van Kuppeveld
authors.affiliation: Incurable Diseases Therapeutics Research Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, South Korea; Department of Biomolecular Science, Korea University of Science and Technology, Daejeon, South Korea. Electronic address: sungchan@kribb.re.kr.
authors.forename: Sungchan
authors.initials: S
authors.lastname: Cho
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004770:Enterovirus / Q000187:drug effects* / Q000502:physiology; D029821:Enterovirus A, Human / Q000187:drug effects / Q000502:physiology; D004769:Enterovirus Infections / Q000188:drug therapy / Q000821:virology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D012093:Replicon / Q000187:drug effects; D012254:Ribavirin / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000998:Antiviral Agents; D003841:Deoxycytidine; D012254:Ribavirin; D000093542:Gemcitabine
keywords: Antiviral inhibitor; Enteroviruses; Gemcitabine; Ribavirin