Medical School of Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
Eur J Med Chem. 2019 Nov 15;182:111622. doi: 10.1016/j.ejmech.2019.111622. Epub 2019 Aug 13.
The development of entry inhibitors is an emerging approach to the inhibition of influenza virus. In our previous research, oleanolic acid (OA) was discovered as a mild influenza hemagglutinin (HA) inhibitor. Herein, as a further study, we report the preparation of a series of OA-saccharide conjugates via the CuAAC reaction, and the anti-influenza activity of these compounds was evaluated in vitro. Among them, compound 11b, an OA-glucose conjugate, showed a significantly increased anti-influenza activity with an IC of 5.47 μM, and no obvious cytotoxic effect on MDCK cells was observed at 100 μM. Hemagglutination inhibition assay and docking experiment indicated that 11b might interfere with influenza virus infection by acting on HA protein. Broad-spectrum anti-influenza experiments showed 11b to be robustly potent against 5 different strains, including influenza A and B viruses, with IC values at the low-micromole level. Overall, this finding further extends the utility of OA-saccharide conjugates in anti-influenza virus drug design.
抑制剂的开发是抑制流感病毒的一种新兴方法。在我们之前的研究中，发现齐墩果酸（OA）是一种温和的流感血凝素（HA）抑制剂。在此基础上，作为进一步的研究，我们通过 CuAAC 反应制备了一系列 OA-糖缀合物，并在体外评估了这些化合物的抗流感活性。其中，OA-葡萄糖缀合物 11b 表现出显著增强的抗流感活性，IC 值为 5.47 μM，在 100 μM 时对 MDCK 细胞没有明显的细胞毒性作用。血凝抑制试验和对接实验表明，11b 可能通过作用于 HA 蛋白干扰流感病毒感染。广谱抗流感实验表明，11b 对包括甲型和乙型流感病毒在内的 5 种不同株系具有强大的活性，IC 值处于低毫摩尔水平。总的来说，这一发现进一步扩展了 OA-糖缀合物在抗流感病毒药物设计中的应用。
