title: An adenosine nucleoside analogue NITD008 inhibits EV71 proliferation.
abstract: Enterovirus 71 (EV71), one of the major causative agents of Hand-Foot-Mouth Disease (HFMD), causes severe pandemics and hundreds of deaths in the Asia-Pacific region annually and is an enormous public health threat. However, effective therapeutic antiviral drugs against EV71 are rare. Nucleoside analogues have been successfully used in the clinic for the treatment of various viral infections. We evaluated a total of 27 nucleoside analogues and discovered that an adenosine nucleoside analogue NITD008, which has been reported to be an antiviral reagent that specifically inhibits flaviviruses, effectively suppressed the propagation of different strains of EV71 in RD, 293T and Vero cells with a relatively high selectivity index. Triphosphorylated NITD008 (ppp-NITD008) functions as a chain terminator to directly inhibit the RNA-dependent RNA polymerase activity of EV71, and it does not affect the EV71 VPg uridylylation process. A significant synergistic anti-EV71 effect of NITD008 with rupintrivir (AG7088) (a protease inhibitor) was documented, supporting the potential combination therapy of NITD008 with other inhibitors for the treatment of EV71 infections.
authors.affiliation: College of Pharmacy & State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China.
authors.forename: Luqing
authors.initials: L
authors.lastname: Shang
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China.
authors.forename: Yaxin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Qing
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Shu
authors.affiliation: College of Pharmacy & State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China; School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Cao
authors.affiliation: School of Medicine, Tsinghua University, Beijing 100084, China; Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lou
authors.affiliation: State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Gong
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China. Electronic address: sunyn@moon.ibp.ac.cn.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Sun
authors.affiliation: College of Pharmacy & State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. Electronic address: zheng_yin@nankai.edu.cn.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004357:Drug Synergism; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives; D011760:Pyrrolidinones / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors; D014633:Valine / Q000031:analogs & derivatives; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D007555:Isoxazoles; C000593137:NITD008; D011760:Pyrrolidinones; D010649:Phenylalanine; D012324:RNA-Dependent RNA Polymerase; D014633:Valine; D000241:Adenosine; C118874:rupintrivir
keywords: Enterovirus 71; NITD008; Nucleoside analogue; Polymerase