Drug Discovery for Schistosomiasis Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening 英文参考文献.docVIP

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Drug Discovery for Schistosomiasis Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening 英文参考文献.doc

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Drug Discovery for Schistosomiasis Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening 英文参考文献

DrugDiscoveryforSchistosomiasis:HitandLead CompoundsIdentifiedinaLibraryofKnownDrugsby Medium-ThroughputPhenotypicScreening Maha-HamadienAbdulla1.,DebbieS.Ruelas1.,BrianWolff2,JuneSnedecor2,Kee-ChongLim1 ,Fengyun Xu1,AdamR.Renslo2,JaniceWilliams2,JamesH.McKerrow1,ConorR.Caffrey1* 1SandlerCenterforBasicResearchinParasiticDiseases,CaliforniaInstituteforQuantitativeBiosciences(QB3),UniversityofCalifornia,SanFrancisco,California,United StatesofAmerica,2SmallMoleculeDiscoveryCenter,CaliforniaInstituteforQuantitativeBiosciences(QB3),UniversityofCalifornia,SanFrancisco,California,UnitedStates ofAmerica Abstract Background: Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance,itisprudenttosearchfornoveltherapeutics.Identificationofanti-schistosomalchemicalshastraditionallyrelied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease—tools that limit automationandthroughputwithmodernmicrotiterplate-formattedcompoundlibraries. Methods: A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomularstageoftheparasiteadaptedtoa96-wellplateformatwithathroughputof640compoundspermonth. Hitsthatarisearesubsequentlyscreenedinvitroagainstadultparasitesandfinallyforefficacyinamurinemodelofdisease. TwoGO/NOGOcriteriafiltersintheworkflowprioritizehitcompoundsfortestsintheanimaldiseasemodelinaccordance with a target drug profile that demands short-course oral therapy. The screen workflow was inaugurated with 2,160 chemicallydiversenaturalandsyntheticcompounds,ofwhich821aredrugsalreadyapprovedforhumanuse.Thisaffordsa uniquestartingpointto‘reposition’(re-profile)drugsasanti-schistosomalswithpotentialsavingsindevelopmenttimelines andcosts. Findings:Multipleanddynamicphenotypescouldbecategorizedforschistosomulaandadultsinvitro,andadiversesetof ‘hit’drugsandchemistrieswereidentified,includinganti-schistosomals,anthelmintics