JACS:艾滋病毒天然屏障或被打开！

 

新研究揭示了朗格汉斯蛋白如何作为感染艾滋病毒第一阶段的自然屏障存在于生殖器分泌液中，期间与药物肝素相互作用。

 

研究小组已经鉴定了朗格汉斯蛋白和肝素之间不同机制的相互作用。东安格利亚大学药学学院博士研究员JesusAngulo说：“朗格汉斯蛋白存在于生殖器粘液中并由免疫细胞产生。艾滋病病毒在感染人的过程中朗格汉斯蛋白组成了第一道屏障。肝素是一种抗凝剂，用来防止血栓的形成。但它也在体内自然生成，并且带有不同成分包绕着我们的细胞。”

 

“朗格汉斯蛋白与肝素的交互作用对HIV病毒退化来说是非常重要的。肝素与朗格汉斯蛋白交互的方式很重要，因为它被认为可以稳定颗粒的形成，有利于消除艾滋病毒颗粒。”

 

“这是一个基本的研究，该研究提供了一个已知HIV天然屏障潜在交互作用的细节结构。然而，这并不意味着服用肝素或其他抗凝药物会保护人们免受艾滋病毒的侵扰。”

 

“这一研究的最终目的是开发抑制促感染艾滋病毒细胞受体的药物，该药并能促进朗格汉斯蛋白活性。抗艾滋药物的研制显然是一个长期目标，而该研究提供了重要的制药初始步骤。”

 

doi:10.1021/ja511529x

 

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Langerin–HeparinInteraction:TwoBindingSitesforSmallandLargeLigandsAsRevealedbyaCombinationofNMRSpectroscopyandCross-LinkingMappingExperiments.

 

JuanC.Mu?oz-García,EricChabrol,RomainR.Vivès,AlineThomas,JoséL.dePaz,JavierRojo,AnneImberty,FranckFieschi,PedroM.Nieto,JesúsAngulo.

 

LangerinisaC-typelectinpresentonLangerhanscellsthatmediatescaptureofpathogensinacarbohydrate-dependentmanner,leadingtosubsequentinternalizationandeliminationinthecellularorganellescalledBirbeckgranules.ThismechanismmediatedbylangerinwasshowntoconstituteanaturalbarrierforHIV-1particletransmission.Besidesinteractingspecificallywithhighmannoseandfucosylatedneutralcarbohydratestructures,langerinhastheabilitytobindsulfatedcarbohydrateligandsas6-sulfatedgalactosidesintheCa2+-dependentbindingsite.Veryrecentlylangerinwasdemonstratedtointeractwithsulfatedglycosaminoglycans(GAGs),inaCa2+-independentway,resultingintheproposalofanewbindingsiteforGAGs.Onthebasisofthoseresults,wehaveconductedastructuralstudyoftheinteractionsofsmallheparin(HEP)-likeoligosaccharideswithlangerininsolution.Heparinbeadcross-linkingexperiments,anapproachspecificallydesignedtoidentifyHEP/heparansulfatebindingsitesinproteinswerefirstcarriedoutandexperimentallyvalidatedthepreviouslyproposedmodelfortheinteractionoflangerinextracellulardomainwith6kDaHEP.High-resolutionNMRstudiesofasetofeightsyntheticHEP-liketrisaccharidesharboringdifferentsulfationpatternsdemonstratedthatallofthemboundtolangerininaCa2+-dependentway.ThebindingepitopesweredeterminedbysaturationtransferdifferenceNMRandtheboundconformationsbytransferredNOESYexperiments.Theseexperimentaldatawerecombinedwithdockingandmoleculardynamicsandresultedintheproposalofabindingmodecharacterizedbythecoordinationofcalciumbythetwoequatorialhydroxylgroups,OH3andOH4,atthenon-reducingend.Thebindingalsoincludesthecarboxylategroupattheadjacentiduronateresidue.Thisepitopeissharedbyalleightligands,substitutionpatterns.Finally,incontrasttothesmalltrisaccharides,wedemonstratedthatalongerHEP-likehexasaccharide,bearinganadditionalO-sulfategroupatthenon-reducingend,whichprecludesbindingtotheCa2+site,interactswithlangerininthepreviouslyidentifiedCa2+-independentbindingsite