2. Academic Validation
  3. Discovery of highly potent and selective influenza virus neuraminidase inhibitors targeting 150-cavity

Discovery of highly potent and selective influenza virus neuraminidase inhibitors targeting 150-cavity

  • Eur J Med Chem. 2021 Feb 15;212:113097. doi: 10.1016/j.ejmech.2020.113097.
Ruifang Jia 1,  Jian Zhang 2,  Chiara Bertagnin 3,  Srinivasulu Cherukupalli 1,  Wei Ai 1,  Xiao Ding 1,  Zhuo Li 1,  Jiwei Zhang 1,  Han Ju 1,  Xiuli Ma 4,  Arianna Loregian 3,  Bing Huang 5,  Peng Zhan 6,  Xinyong Liu 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China.
  • 2 Institute of Medical Sciences, The Second Hospital, Cheeloo College of Medicine, Shandong University, 250033, PR China.
  • 3 Department of Molecular Medicine, University of Padova, via Gabelli 63, 35121, Padova, Italy.
  • 4 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan, Shandong, 250023, PR China.
  • 5 Institute of Poultry Science, Shandong Academy of Agricultural Sciences, 1 Jiaoxiao Road, Jinan, Shandong, 250023, PR China. Electronic address: hbind@163.com.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 7 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, PR China; China-Belgium Collaborative Research Center for Innovative Antiviral Drugs of Shandong Province, 44 West Culture Road, 250012, Jinan, Shandong, PR China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 33385836 DOI: 10.1016/j.ejmech.2020.113097
Abstract

Encouraged by our earlier discovery of N1-selective inhibitors, the 150-cavity of Influenza Virus neuraminidases (NAs) could be further exploited to yield more potent oseltamivir derivatives. Herein, we report the design, synthesis and biological evaluation of a series of novel oseltamivir derivatives via the structural modifications at C5-NH2 of oseltamivir targeting 150-cavity. Among them, compound 5c bearing 4-(3-methoxybenzyloxy)benzyl group exhibited the most potent activity, which was lower or modestly improved activities than oseltamivir carboxylate (OSC) against N1 (H1N1), N1 (H5N1) and N1 (H5N1-H274Y). Specifically, there was 30-fold loss of activity against the wild-type strain H1N1. However, 5c displayed 4.85-fold more potent activity than OSC against H5N1-H274Y NA. Also, 5c demonstrated low cytotoxicity in vitro and no acute toxicity in mice. Molecular docking studies provided insights into the high potency of 5c against N1 and N1-H274Y mutant NAs. Besides, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability of representative compounds were conducted to evaluate their drug-like properties.

Keywords

150-Cavity; Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives.

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