2. Academic Validation
  3. Identification of dibucaine derivatives as novel potent enterovirus 2C helicase inhibitors: In vitro, in vivo, and combination therapy study

Identification of dibucaine derivatives as novel potent enterovirus 2C helicase inhibitors: In vitro, in vivo, and combination therapy study

  • Eur J Med Chem. 2020 Sep 15:202:112310. doi: 10.1016/j.ejmech.2020.112310.
Qi Tang 1,  Zhichao Xu 2,  Mengyu Jin 2,  Ting Shu 3,  Yinuo Chen 1,  Leilei Feng 1,  Qiuhan Zhang 1,  Ke Lan 4,  Shuwen Wu 5,  Hai-Bing Zhou 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 2 Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China.
  • 3 State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, 430071, China.
  • 4 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China; Medical Research Institute, Wuhan University, Wuhan, 430071, China. Electronic address: klan@whu.edu.cn.
  • 5 State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China. Electronic address: shuwenwu@hotmail.com.
  • 6 Hubei Province Engineering and Technology Research Center for Fluorinated Pharmaceuticals, Frontier Science Center for Immunology and Metabolism, Wuhan University School of Pharmaceutical Sciences, Wuhan, 430071, China. Electronic address: zhouhb@whu.edu.cn.
PMID: 32619885 DOI: 10.1016/j.ejmech.2020.112310
Abstract

Enterovirus A71 (EV-A71) is a human pathogen causing hand, foot and mouth disease (HFMD) which seriously threatened the safety and lives of infants and young children. However, there are no licensed direct Antiviral agents to cure the HFMD. In this study, a series of quinoline formamide analogues as effective Enterovirus inhibitors were developed, subsequent systematic structure-activity relationship (SAR) studies demonstrated that these quinoline formamide analogues exhibited good potency to treat EV-A71 Infection. As described, the most efficient EV-A71 inhibitor 6i showed good anti-EV-A71 activity (EC50 = 1.238 μM) in RD cells. Furthermore, compound 6i could effectively prevent death of virus infected mice at dose of 6 mg/kg. When combined with emetine (0.1 mg/kg), this treatment could completely prevent the clinical symptoms and death of virus infected mice. Mechanism study indicated that compound 6i inhibited EV-A71 via targeting 2C helicase, thus impeding RNA remodeling and metabolism. Taken together, these data indicated that 6i is a promising EV-A71 inhibitor and worth extensive preclinical investigation as a lead compound.

Keywords

2C Helicase inhibitor; Combination therapy; EV-A71; In vivo study; Structure-activity relationship.

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