PNAS:中国“蜱虫病”病毒现原型暴“阿喀琉斯之踵”
先科普一个,啥叫阿喀琉斯之踵?
阿喀琉斯之踵(Achilles'Heel),原指阿喀琉斯的脚跟,现一般用于指致命的弱点,要害。
导读:近日,中国科学院微生物研究所高福院士团队与中国科学院
遗传与
发育生物学研究所高峰博士首次解析了两种布尼亚病毒囊膜蛋白Gn的结构以及其中一种重要病原新布尼亚病毒(又称发热伴血小板减少综合征病毒,SevereFeverwithThrombocytopeniaSyndromeVisus,SFTSV)的Gn与中和抗体的复合物结构,为
疫苗与
抗病毒药物的研发提供了重要的理论依据。
文章解读:布尼亚病毒是一种具有囊膜的单链RNA病毒,具有三个RNA片段(S,M和L)。其中M基因编码囊膜蛋白Gn和Gc,在病毒侵入宿主细胞的过程中起重要作用。之前的研究推测Gn在病毒侵入宿主细胞过程中有可能起识别受体的作用。该研究团队首次解析了裂谷热病毒和新布尼亚病毒囊膜蛋白Gn的头部区结构,发现这两种Gn的头部区的整体结构十分相似,均由三个亚结构域组成,但是亚结构域存在差异。对于SFTSVGn全长蛋白的研究发现该蛋白同时存在单体和二聚体两种形式。质谱分析和突变实验结果显示靠近C末端的4个半胱氨酸是形成二硫键的关键位点,这4个半胱氨酸在5个布尼亚病毒属(按照ICTV最新分类分别为Hantaviridae,Nairoviridae,Tospoviridae病毒科和Phenuiviridae科白蛉属以及Peribunyaviridae科正布尼亚病毒属)的成员间非常保守,由此提出布尼亚病毒囊膜蛋白Gn在病毒表面以二聚体形式存在的模型。
图1.白蛉属布尼亚病毒囊膜蛋白Gn在病毒表面锚定方式模式图
研究人员进一步解析了SFTSVGn与中和抗体MAb4-5的复合物结构,发现Gn的domainIII的α6螺旋是中和抗体MAb4-5识别的关键表位(图2)。序列分析结果显示该表位在白蛉属的其他布尼亚病毒中并不保守,解释了该中和抗体特异性结合SFTSVGn,不结合RVFVGn的原因。SFTSVGn与抗体的复合物结构阐明了两者的作用模式,为疫苗及抗病毒药物的设计、抗体改造提供了理论依据。
Abstract:Severefeverwiththrombocytopeniasyndromevirus(SFTSV)andRiftValleyfevervirus(RVFV)aretwoarthropod-bornephlebovirusesintheBunyaviridaefamily,whichcausesevereillnessinhumansandanimals.GlycoproteinN(Gn)isoneoftheenvelopeproteinsonthevirussurfaceandisamajorantigeniccomponent.Despiteitsimportanceforvirusentryandfusion,themolecularfeaturesofthephleboviruseGnwereunknown.Here,wepresentthecrystalstructuresoftheGnheaddomainfrombothSFTSVandRVFV,whichdisplayasimilarcompacttriangularshapeoverall,whilethethreesubdomains(domainsI,II,andIII)makinguptheGnheaddisplaydifferentarrangements.TencysteinesintheGnstemregionareconservedamongphleboviruses,fourofwhichareresponsibleforGndimerization,asrevealedinthisstudy,andtheyarehighlyconservedforallmembersinBunyaviridaeTherefore,weproposeananchoringmodeontheviralsurface.ThecomplexstructureoftheSFTSVGnheadandhumanneutralizingantibodyMAb4-5revealsthathelicesα6insubdomainIIIisthekeycomponentforneutralization.Importantly,thestructureindicatesthatdomainIIIisanidealregionrecognizedbyspecificneutralizingantibodies,whiledomainIIisprobablyrecognizedbybroadlyneutralizingantibodies.Collectively,Gnisadesirablevaccinetarget,andourdataprovideamolecularbasisfortherationaldesignofvaccinesagainstthediseasescausedbyphlebovirusesandamodelforbunyavirusGnembeddingontheviralsurface.
武汉病毒所成功筛选得到阻断乙脑病毒感染的小分子药物
文章导读:中国科学院武汉病毒研究所肖庚富课题组在JournalofVirology发文,该课题组通过对美国食品和药物管理局(FoodandDrugAdministration,FDA)批准的1018种药物的筛选,得到5种对乙脑病毒(Japaneseencephalitisvirus,JEV)的治疗指数大于10的小分子药物,分别是马尼地平、西尼地平、盐酸贝尼地平、吡美莫司和奈非那韦。研究人员证实了5种FDA批准药物在体内和体外均能有效抑制JEV感染,基于其明确的作用靶点,高效的病毒抑制率以及良好的生物相容性,本实验提供了高效的可用于临床治疗JEV和黄病毒科感染的药物。
Abstract:Japaneseencephalitisvirus(JEV),anarthropod-borneflavivirus,isamajorcauseofacuteviralencephalitisinhumans.ThereisnoapproveddrugavailableforJEV-specifictreatment,andthevaccinesarenoteffectiveagainstallclinicalJEVisolates.Herein,ahigh-throughputscreeningwasperformedagainstJEVfromanFDA-approveddruglibrary.FivehitdrugswereidentifiedthatinhibitedJEVinfectionwithaselectiveindex>10.Antiviralactivitiesofthesefivehitdrugsagainstotherflavivirus,includingZikavirus,werealsovalidated.Asthreeofthefivehitdrugswerecalciuminhibitors,additionaltypesofcalciuminhibitorswereutilizedthatconfirmedcalciumwasessentialforJEVinfection,mostlikelyduringviralreplication.AdaptivemutantanalysisuncoveredthatreplacementofQ130,locatedintran
smembranedomain3ofthenon-structuralNS4Bproteinwhilerelativelyconservedinflavivirus,withRorKconferredJEVresistancetomanidipine,avoltage-gatedCa2+channel(VGCC)inhibitor,withoutapparentlossoftheviralgrowthprofile.Furthermore,manidipinewasindicatedtoprotectmiceagainstJEV-inducedlethalitybydecreasingviralloadinbrain,whileabrogatinghistopathologicalchangesassociatedwithJEVinfection.Thisstudyprovidedfiveanti-flaviviruscandidatesandidentifiedcytoplasmiccalciumasanovelantiviraltargetfortreatmentofJEVinfection.Thefindingsreportedhereprovidetherapeuticpossibilitiesforcombatinginfectionscausedbyflavivirus.
IMPORTANCE:CurrentlythereisnoapprovedtherapytotreatJapaneseEncephalitisVirusinfection.Repurposingoftheapproveddrugswillacceleratethedevelopmentofthetherapeuticstratagem.Inthisstudy,wescreenedanFDA-drugslibraryandidentifiedfivehitdrugs,especiallycalciuminhibitors,exertinganti-flavivirusactivitythatblockedviralreplication.TheinvivoefficacyandtoxicityofmanidipinewereinvestigatedwithaJEV-infectedmousemodelandtheviraltargetwasidentifiedbygeneratingadaptivemutant.