Protection against Retrovirus Pathogenesis by SR Protein Inhibitors 英文参考文献.docVIP

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Protection against Retrovirus Pathogenesis by SR Protein Inhibitors 英文参考文献.doc

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Protection against Retrovirus Pathogenesis by SR Protein Inhibitors 英文参考文献

ProtectionagainstRetrovirusPathogenesisbySRProtein Inhibitors AnneKeriel1,FlorenceMahuteau-Betzer2,ChantalJacquet1,MarcPlays1,DavidGrierson3 ,Marc Sitbon1*,JamalTazi1* 1Universite′Montpellier2Universite′Montpellier1CNRS,InstitutdeGe′ne′tiqueMole′culairedeMontpellier(IGMM),UMR5535,IFR122,Montpellier,France,2Laboratoirede Pharmaco-chimie, CNRS-Institut Curie, UMR 176 Bat 110 Centre Universitaire, Orsay, France, 3Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver,BritishColumbia,Canada Abstract Indole derivatives compounds (IDC) are a new class of splicing inhibitors that have a selective action on exonic splicing enhancers (ESE)-dependent activity of individual serine-arginine-rich (SR) proteins. Some of these molecules have been showntocompromiseassemblyofHIVinfectiousparticlesincellculturesbyinterferingwiththeactivityoftheSRprotein SF2/ASF and by subsequently suppressing production of splicing-dependent retroviral accessory proteins. For all replication-competentretroviruses,alimitingrequirementforinfectionandpathogenesisistheexpressionoftheenvelope glycoproteinwhichstrictlydependsonthehostsplicingmachinery.Here,wehaveevaluatedtheefficiencyofIDConan animal model of retroviral pathogenesis using a fully replication-competent retrovirus. In this model, all newborn mice infectedwithafullyreplicativemurineleukemiavirus(MLV)developerythroleukemiawithin6to8weeksofage.Wetested severalIDCfortheirabilitytointerfereexvivowithMLVsplicingandvirusspreadingaswellasfortheirprotectiveeffectin vivo. We show here that two of these IDC, IDC13 and IDC78, selectively altered splicing-dependent production of the retroviral envelope gene, thus inhibiting early viral replication in vivo, sufficiently to protect mice from MLV-induced pathogenesis.TheapparentspecificityandclinicalsafetyobservedhereforbothIDC13andIDC78stronglysupportfurther assessmentofinhibitorsofSRproteinsplicingfactorsasanewclassofantiretroviraltherapeuticagents. Citation: Keriel A, Mahuteau-B