A Small Molecule Inhibitor of Signal Peptide Peptidase Inhibits Plasmodium Development in the Liver and Decreases Malaria Severity 英文参考文献.docVIP

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A Small Molecule Inhibitor of Signal Peptide Peptidase Inhibits Plasmodium Development in the Liver and Decreases Malaria Severity 英文参考文献.doc

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A Small Molecule Inhibitor of Signal Peptide Peptidase Inhibits Plasmodium Development in the Liver and Decreases Malaria Severity 英文参考文献

ASmallMoleculeInhibitorofSignalPeptidePeptidase InhibitsPlasmodiumDevelopmentintheLiverand DecreasesMalariaSeverity IanaParvanova1¤,SabrinaEpiphanio1,AbdulFauq2,ToddE.Golde2,MiguelPrude?ncio1,3,MariaM. Mota1,3 * 1UnidadedeMala′ria, InstitutodeMedicinaMolecular,FaculdadedeMedicinadaUniversidadedeLisboa,Lisboa,Portugal,2DepartmentofNeuroscience,MayoClinic, CollegeofMedicine,Jacksonville,Florida,UnitedStatesofAmerica,3InstitutoGulbenkiandeCie?ncia,Oeiras,Portugal Abstract TheliverstageofPlasmodium’slifecycleisthefirst,obligatorystepinmalariainfection.Decreasingthehepaticburdenof Plasmodiuminfectiondecreasestheseverityofdiseaseandconstitutesapromisingstrategyformalariaprophylaxis. The efficacyofthegamma-secretaseandsignalpeptidepeptidaseinhibitorLY411,575intargetingPlasmodiumliverstageswas evaluated both in human hepatoma cell lines and in mouse primary hepatocytes. LY411,575 was found to prevent Plasmodium’snormaldevelopmentintheliver,withanIC50ofapproximately80nM,withoutaffectinghepatocyteinvasion bytheparasite.InvivoresultswitharodentmodelofmalariashowedthatLY411,575decreasestheparasiteloadintheliver andincreasesby55%theresistanceofmicetocerebralmalaria,oneofthemostseveremalaria-associatedsyndromes.Our datashowthatLY411,575doesnotexertitseffectviatheNotchsignalingpathwaysuggestingthatitmayinterferewith Plasmodium development through an inhibition of the parasite’s signal peptide peptidase. We therefore propose that selectivesignalpeptidepeptidaseinhibitorscouldbepotentiallyusedforpreventivetreatmentofmalariainhumans. Citation: Parvanova I, Epiphanio S, Fauq A, Golde TE, Prude?ncio M, et al. (2009) A Small Molecule Inhibitor of Signal Peptide Peptidase Inhibits Plasmodium DevelopmentintheLiverandDecreasesMalariaSeverity.PLoSONE4(4):e5078.doi:10.1371/journal.pone.0005078 Editor:GordonLangsley,INSERMU567,InstitutCochin,France ReceivedDecember17,2008;AcceptedMarch5,2009;PublishedApril1,2009 Copyright: ?2009 Parvanova et al. This is an open-access article dist