2. Academic Validation
  3. Synthesis, structure activity relationship and in vitro anti-influenza virus activity of novel polyphenol-pentacyclic triterpene conjugates

Synthesis, structure activity relationship and in vitro anti-influenza virus activity of novel polyphenol-pentacyclic triterpene conjugates

  • Eur J Med Chem. 2019 Feb 1:163:560-568. doi: 10.1016/j.ejmech.2018.12.006.
Haiwei Li 1,  Man Li 1,  Renyang Xu 1,  Shouxin Wang 2,  Yongmin Zhang 3,  Lihe Zhang 1,  Demin Zhou 4,  Sulong Xiao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
  • 2 School of Pharmacy, Jining Medical University, Rizhao 276826, China.
  • 3 Sorbonne Université, Institut Parisien de Chimie Moléculaire, CNRS UMR 8232, 4 place Jussieu, 75005 Paris, France.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: deminzhou@bjmu.edu.cn.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China. Electronic address: slxiao@bjmu.edu.cn.
PMID: 30554131 DOI: 10.1016/j.ejmech.2018.12.006
Abstract

It is urgently necessary to develop more effective anti-influenza agents due to the continuous emergence of drug-resistant strains of Influenza Virus. Our earlier studies have identified that certain pentacyclic triterpene derivatives are effective inhibitors of Influenza Virus infection. In the present study, a series of C-28 modified pentacyclic triterpene derivatives via conjugation with a series of Polyphenols were synthesized, and their Antiviral activities against influenza A/WSN/33 (H1N1) virus in MDCK (Madin-Darby canine kidney) cells were evaluated. Four compounds 23m, 23o, 23q and 23s displayed robust anti-influenza potency with averaged IC50 values at the low-micromole level, surpassing the potency of oseltamivir. In addition, the in vitro cytotoxic activity of the four conjugates against MDCK cells showed no toxicity at 100 μM. Further mechanism studies of compound 23s, one of the best representative conjugates with IC50 value of 5.80 μM and a selective index (SI) value of over 17.2, by hemagglutination inhibition (HI), surface plasmon resonance and molecular modeling indicated that this conjugate bound tightly to the viral envelope hemagglutinin (KD = 15.6 μM), thus blocking the invasion of influenza viruses into host cells.

Keywords

Entry inhibitor; Hemagglutinin; Influenza virus; Pentacyclic triterpene; Polyphenol.

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