γ-环糊精-五环三萜多价偶联物——通过多价效应抑制流感病毒进入细胞的新型分子
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- 英文论文题名：Synthesis and Biological Evaluation of Multivalent γ-Cyclodextrin-Pentacyclic Triterpene Conjugates as Influenza Virus Entry Inhibitors
- 论文作者：田振宇 ; 司龙龙 ; 周德敏 ; 肖苏龙
- 英文论文作者：Tian Zhen-yu ; Si Long-long ; Zhou De-min ; Xiao Su-long ; State Key Laboratory of Natural and Biomimetic Drugs ; School of Pharmaceutical Sciences ; Peking University
- 年：2016
- 作者机构：天然药物及仿生药物国家重点实验室,北京大学药学院;
- 论文关键词：五环三萜 ; γ-环糊精 ; 多价效应 ; 抗流感病毒进入
- 英文论文关键词：pentacyclic triterpene ; γ-cyclodextrin(γ-CD) ; multivalent effect ; anti-influenza entry inhibitor
- 会议召开时间：2016-09-27
- 会议录名称：中国药学会第十三届青年药学科研成果交流会论文集
- 语种：中文
- 分类号：R96;R914.5
- 学会代码：YYWS
- 会议名称：中国药学会第十三届青年药学科研成果交流会
- 会议地点：中国江西南昌
- 主办单位：中国药学会
- 学会名称：中国药学会
- 页数：4
- 文件大小：356k
- 原文格式：O
- 会议级别：全国
摘要
目的设计并合成以γ-环糊精为骨架的五环三萜多价偶联物,并研究其抗流感病毒活性及机制。方法通过微波辅助及铜催化的点击化学(CuAAC)反应将多个五环三萜分子与γ-环糊精进行高效偶联;通过细胞病变抑制实验评价其抗流感病毒的活性;通过加药时间点及间接免疫荧光实验初步探索了其抗流感病毒的机理。结果与结论合成了多个五环三萜-γ-环糊精多价偶联物,该类化合物能阻断病毒HA蛋白与宿主细胞的结合,具有明显的抗H1N1病毒进入的活性,有可能成为新型结构的抗流感病毒候选药物。
OBJECTIVE To synthesize the multivalent y-cyclodextrin-pentacyclic triteipene conjugates and evaluate their anti-influenza entry activity.METHODS The conjugates were synthesized by the copper-catalyzed alkyne-azide cycloaddition(CuAAC) reaction between an alkyne-labeled pentacyclic triteipene and multi-azide-substituted y-cyclodextrin scaffold.The cytopathic effect(CPE) reduction assay and the Cell Titer-Glo assay were conducted to evaluate the anti-influenza activity and toxicity,respectively.Furthermore,the time-of-addition and the attachment assay experiments were used to explore the mechanism.RESULTS AND CONCLUSION Some of these multivalent conjugates display strong anti-influenza virus activity.Further mechanism exploration indicated that they disrupted the interaction of HA with the SA receptor and thus blocked the attachment of viruses to host cells.This study may establish a strategy for the design of new anti-influenza pharmaceutical agents.
OBJECTIVE To synthesize the multivalent y-cyclodextrin-pentacyclic triteipene conjugates and evaluate their anti-influenza entry activity.METHODS The conjugates were synthesized by the copper-catalyzed alkyne-azide cycloaddition(CuAAC) reaction between an alkyne-labeled pentacyclic triteipene and multi-azide-substituted y-cyclodextrin scaffold.The cytopathic effect(CPE) reduction assay and the Cell Titer-Glo assay were conducted to evaluate the anti-influenza activity and toxicity,respectively.Furthermore,the time-of-addition and the attachment assay experiments were used to explore the mechanism.RESULTS AND CONCLUSION Some of these multivalent conjugates display strong anti-influenza virus activity.Further mechanism exploration indicated that they disrupted the interaction of HA with the SA receptor and thus blocked the attachment of viruses to host cells.This study may establish a strategy for the design of new anti-influenza pharmaceutical agents.
引文
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[2]Waldmann,M.;Jirmann,R.;Hoelscher,K.;et al.A nanomolar multivalent ligand as entry inhibitor of the hemagglutinin of avian influenza[J].J.Am.Chem.Soc,2014,136:783-788
[3]Decroocq,C;Rodriguez,L.D.;Russo,V.;et al.The multivalent effect in glycosidase inhibition:probing the influence of architectural parameters with cyclodextrin-based iminosugar click clusters[J].Chem.Eur.J.2011,17:13825-13831
[4]M.R.Yu,L.L.Si,Y.F."Wang,Y.M.Wu,F.Yu,RX.Jiao,et al.,Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses[J].J.Med.Chem,2014,57(23):10058-10071.
[5]N.Sharma,A.Baldi,Exploring versatile applications of cyclodextrins:an Overview[J].Drug Deliv,2015:1-19.
[6]Baer HH,Berenguel AV,Shu YY,Defaye J,Gadelle A,Gonzalez FS.Improved preparation of hexakis(6-deoxy)cyclomalto-hexaose and heptakis(6-deoxy)cyclomaltoheptaose[J].Carbohydr Res,1992,228(1):307-14
[7]Xiao S L,Si L L,Tian Z Y,et al.Pentacyclic triterpenes grafted on CD cores to interfere with influenza virus entry:A dramatic multivalent effect[J].Biomaterials,2016,78:74-85.