State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
School of Pharmacy, Jining Medical University, Rizhao 276826, China.
Eur J Med Chem. 2019 Feb 1;163:560-568. doi: 10.1016/j.ejmech.2018.12.006. Epub 2018 Dec 7.
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 IC 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 IC 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 (K = 15.6 μM), thus blocking the invasion of influenza viruses into host cells.
由于流感病毒耐药株的不断出现，迫切需要开发更有效的抗流感药物。我们之前的研究已经确定，某些五环三萜衍生物是有效的流感病毒感染抑制剂。在本研究中，通过与一系列多酚缀合，合成了一系列 C-28 修饰的五环三萜衍生物，并在 MDCK（Madin-Darby 犬肾）细胞中评估了它们对甲型流感病毒/WSN/33（H1N1）的抗病毒活性。四种化合物 23m、23o、23q 和 23s 表现出强大的抗流感活性，平均 IC 值处于低微摩尔水平，超过了奥司他韦的活性。此外，四种缀合物对 MDCK 细胞的体外细胞毒性在 100µM 时没有显示出毒性。通过血凝抑制（HI）、表面等离子体共振和分子建模进一步研究化合物 23s（一种具有 5.80µM 的 IC 值和超过 17.2 的选择性指数（SI）的最佳代表性缀合物之一）的机制，表明该缀合物与病毒包膜血凝素紧密结合（K=15.6µM），从而阻止流感病毒侵入宿主细胞。
