State Key Laboratory of Phytochemistry and Plant Resources in West China, and Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, People' s Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.
The Fifth Department of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, People's Republic of China.
Bioorg Med Chem. 2019 Sep 1;27(17):3846-3852. doi: 10.1016/j.bmc.2019.07.013. Epub 2019 Jul 8.
The stems of Dryopteris crassirhizoma, one of the main components of Lianhua-Qingwen Formula (LQF) was traditionally used for heat-clearing and detoxifying. Dryocrassin ABBA is a key antiviral component in the herbal medicine while the compound is hard to get in large amounts with the features of homologous compounds, polyphenol groups, and low contents. Therefore, the present work aims to seek influenza H7N9 virus inhibitors from natural source by synthesis of dryocrassin ABBA and its analogues. As a result, total synthesis of the compound was achieved in nine steps with an over-all yield of 4.6%. Neuraminidases (NAs) inhibitory activities of the synthesized product and its analogues were evaluated afterward. Comparing with the positive control, OSV (9.6 μM), it was very exciting that dryocrassin ABBA and its analogues (b5 and e2) showed better NAs inhibitory activity against Anhui H7N9 with IC values of 3.6 μM, 2.5 μM and 1.6 μM. For the highly resistant Shanghai N9, these compounds can also show medium inhibitory activities. Docking results indicated the direct interaction of synthesized 3 hits with the key K294 by hydrogen bonds, but no direct interaction of OSV with the key K294 was observed in Shanghai N9. This study suggested that dryocrassin ABBA and its analogues especially AB, which consisted of polyphenol groups may have beneficial effects on treating avian influenza H7N9 virus.
贯众是连花清瘟配方（LQF）的主要成分之一，其根茎历来被用作清热解毒。蛇足石杉中的蛇足杉脂碱 ABBA 是该草药中的一种关键抗病毒成分，但由于其结构与同系物相似、含有多酚基团以及含量较低，因此难以大量获取。因此，本研究旨在通过合成蛇足杉脂碱 ABBA 及其类似物，从天然产物中寻找抗流感 H7N9 病毒的抑制剂。研究结果成功地以 9 步反应实现了化合物的全合成，总收率为 4.6%。随后对合成产物及其类似物的神经氨酸酶（NA）抑制活性进行了评估。与阳性对照物 OSV（9.6 μM）相比，令人非常兴奋的是，蛇足杉脂碱 ABBA 及其类似物（b5 和 e2）对安徽 H7N9 表现出更好的 NA 抑制活性，IC 值分别为 3.6 μM、2.5 μM 和 1.6 μM。对于高耐药性的上海 N9，这些化合物也表现出中等抑制活性。对接结果表明，3 个命中化合物通过氢键与关键的 K294 直接相互作用，而 OSV 与上海 N9 中的关键 K294 则没有直接相互作用。本研究表明，蛇足杉脂碱 ABBA 及其类似物，特别是含有多酚基团的 AB，可能对治疗禽流感 H7N9 病毒具有有益作用。
