沙粒病毒进入宿主细胞阻断剂3,5,6,7,4'-五甲氧基黄酮的发现及机制研究

Effects and mechanism of 3,5,6,7,4'-pentamethoxyflavone for blocking arenavirus entry

沙粒病毒是有包膜的RNA病毒,现已知其家族中的8种病毒可致人出血热。除胡宁病毒疫苗外,目前尚无针对其他沙粒病毒的疫苗或特效药物批准上市。本研究是在首次发现黄酮类化合物桔皮素的抗沙粒病毒活性的基础上,从34个桔皮素类似物中发现并确认了3,5,6,7,4'-五甲氧基黄酮的抗拉沙病毒的活性(EC_(50):5.2μmol·L^(-1)),并初步探讨了其构效关系。研究结果表明, 3,5,6,7,4'-五甲氧基黄酮对拉沙病毒的抑制活性是通过阻断病毒融合过程实现的,该化合物对除拉沙病毒外的另外7种致出血热沙粒病毒进入宿主细胞过程也有阻断活性(EC_(50):0.84～10.2μmol·L^(-1)),其抗毒谱与现有沙粒病毒进入抑制剂相比有明显优势。本研究结果为应对致出血热沙粒病毒的药物研发提供了物质储备,也为寻找和发现广谱抗沙粒病毒活性物质提供线索。

Arenaviruses are enveloped RNA viruses,and eight members in this family are known to cause human hemorrhagic fever.Treatments for the viral hemorrhagic fever(VHF)by arenaviruses are very limited.We have identified the first flavone,tangeretin,with broad-spectrum inhibitory activities on VHF-arenaviruses infection by blocking viral entry.In this study,we evaluated thirty-four tangeretin analogues and found 3,5,6,7,4’-pentamethoxyflavone as a Lassa virus entry inhibitor,with EC50 of 5.2μmol·L-1,by blocking the viral fusion process.The compound 3,5,6,7,4’-pentamethoxyflavone is effective on all known VHF-arenaviruses,with EC50 range of 0.84-10.2μmol·L-1.These results suggest that 3,5,6,7,4’-pentamethoxyflavone is able to serve as a start point for discovery of arenavirus entry inhibitors from flavone natural products.