2. Academic Validation
  3. Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

Optimization of N-Substituted Oseltamivir Derivatives as Potent Inhibitors of Group-1 and -2 Influenza A Neuraminidases, Including a Drug-Resistant Variant

  • J Med Chem. 2018 Jul 26;61(14):6379-6397. doi: 10.1021/acs.jmedchem.8b00929.
Jian Zhang 1,  Vasanthanathan Poongavanam 2,  Dongwei Kang 1,  Chiara Bertagnin 3,  Huamei Lu 4,  Xiujie Kong 1,  Han Ju 1,  Xueyi Lu 1,  Ping Gao 1,  Ye Tian 1,  Haiyong Jia 1,  Samuel Desta 1,  Xiao Ding 1,  Lin Sun 1,  Zengjun Fang 5,  Boshi Huang 1,  Xuewu Liang 1,  Ruifang Jia 1,  Xiuli Ma 4,  Wenfang Xu 1,  Natarajan Arul Murugan 6,  Arianna Loregian 3,  Bing Huang 4,  Peng Zhan 1,  Xinyong Liu 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences , Shandong University , 44 West Culture Road , 250012 Jinan , Shandong , P.R. China.
  • 2 Department of Physics, Chemistry, and Pharmacy , University of Southern Denmark , DK-5230 Odense M. , Denmark.
  • 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 , P. R. China.
  • 5 The Second Hospital of Shandong University , no. 247 Beiyuan Avenue , Jinan 250033 , China.
  • 6 Division of Theoretical Chemistry and Biology, School of Biotechnology , KTH Royal Institute of Technology , S-106 91 Stockholm , Sweden.
PMID: 29965752 DOI: 10.1021/acs.jmedchem.8b00929
Abstract

On the basis of 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. Among the synthesized compounds, 15b and 15c were exceptionally active against both group-1 and -2 NAs. Especially for 09N1, N2, N6, and N9 subtypes, they showed 6.80-12.47 and 1.20-3.94 times greater activity than oseltamivir carboxylate (OSC). They also showed greater inhibitory activity than OSC toward H274Y and E119V variant. In cellular assays, they exhibited greater potency than OSC toward H5N1, H5N2, H5N6, and H5N8 viruses. 15b demonstrated high metabolic stability, low cytotoxicity in vitro, and low acute toxicity in mice. Computational modeling and molecular dynamics studies provided insights into the role of R group of 15b in improving potency toward group-1 and -2 NAs. We believe the successful exploitation of the 150-cavity of NAs represents an important breakthrough in the development of more potent anti-influenza agents.

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