Discovery of dehydroandrographolide derivatives with C19 hindered ether as potent anti-ZIKV agents with inhibitory activities to MTase of ZIKV NS5
Discovery of dehydroandrographolide derivatives with C19 hindered ether as potent anti-ZIKV agents with inhibitory activities to MTase of ZIKV NS5
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DOI：
10.1016/j.ejmech.2022.114710
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发表时间：
2022-08-30
影响因子：
6.7
通讯作者：
Zhou，Guo-Chun
中科院分区：
文献类型：
--
作者：
Qian，Weiyi;Zhou，Guang-Feng;Zhou，Guo-Chun
寨卡病毒（ZIKV）是一种蚊子传播的虫媒病毒，也是黄病毒属的一员，感染ZIKV可能会导致儿童小头畸形和格林-巴利综合征，这仍然是一个持续的全球威胁。ZIKV感染的有效抗病毒药物具有巨大的医疗需求。发现穿心莲内酯及其类似物具有抗黄病毒感染的活性。在这项研究中，我们发现一些3-肟基或3-醇-19-位阻醚的脱水穿心莲内酯衍生物是有效的抗ZIKV药物，具有低细胞毒性（CC 50> 200 μM）。添加时间测定表明化合物5a及其类似物对ZIKV生命周期的进入后阶段起抑制作用。通过实验和分子对接研究发现，3a、5a、5 b和5c的活性抗ZIKV化合物具有ZIKV NS 5 MTase（甲基转移酶）酶活性的抑制活性。初步SAR揭示，具有庞大基团的C19修饰对于抗ZIKV感染和复制是必需的，5a的抗ZIKV活性来自其自身携带受阻三苯甲基醚而不是来自其不稳定性，脱氢穿心莲内酯的主链比穿心莲内酯的主链更有效地对抗ZIKV感染，并且3-肟衍生物比3-醇衍生物更有效地对抗ZIKV感染。据我们所知，5a是首次报道的穿心莲内酯衍生物的MTase抑制剂。更重要的是，发现具有酸稳定的19-OCHPh 2的活性化合物5 b对抗ZIKV感染是有价值的，并且为我们设计和发现通常酸稳定的抗ZIKV剂提供了线索。
Infection by Zika virus (ZIKV), a mosquito-transmitted arbovirus and a member ofFlavivirus, could make pediatric microcephaly and Guillain–Barré syndrome, which remains an ongoing global threat. The efficient antivirals to ZIKV infection are of great medical need. Andrographolide and its analogues were discovered to be active against flaviviral infection. In this study, we discovered some dehydroandrographolide derivatives of 3-oximido- or 3-alcohol-19-hindered ether to be potent anti-ZIKV agents with low cytotoxicities (CC50> 200 μM). Time of addition assay suggests that compound 5a and its analogues act on inhibition of post-entry stage of ZIKV life cycle. It is discovered by experimental and molecular docking studies that active anti-ZIKV compounds of 3a, 5a, 5b and 5c possess inhibitory activities of ZIKV NS5 MTase (methyl transferase) enzymatic activity. Preliminary SAR reveals that C19-modification with bulky groups is necessary for anti-ZIKV infection and replication, anti-ZIKV activity of 5a comes from itself bearing hindered trityl ether but not from its instability, the backbone of dehydroandrographolide is more effective against ZIKV infection than that of andrographolide, and 3-oxime derivatives are more active against ZIKV infection than 3-alcohol derivatives. To our knowledge, 5a is the first reported MTase inhibitor of andrographolide derivatives. More importantly, discovery of active compound 5b with acid-stable 19-OCHPh2against ZIKV infection is valued and gives us a clue to design and discover generally acid-stable anti-ZIKV agents.