Adenosine Kinase of T. b. rhodesiense Identified as the Putative Target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine Using Chemical Proteomics 英文参考文献.docVIP

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Adenosine Kinase of T. b. rhodesiense Identified as the Putative Target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine Using Chemical Proteomics 英文参考文献.doc

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Adenosine Kinase of T. b. rhodesiense Identified as the Putative Target of 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3-yl]morpholine Using Chemical Proteomics 英文参考文献

AdenosineKinaseofT.b.rhodesienseIdentifiedasthe PutativeTargetof4-[5-(4-phenoxyphenyl)-2H-pyrazol-3- yl]morpholineUsingChemicalProteomics SabineKuettel1,MarcMosimann2,PascalMa¨ser2,MarcelKaiser3,RetoBrun3,LeonardoScapozza1*, RemoPerozzo1* 1PharmaceuticalBiochemistryGroup,SchoolofPharmaceuticalSciences,UniversityofGeneva,UniversityofLausanne,Geneva,Switzerland,2InstituteofCellBiology, UniversityofBern,Bern,Switzerland,3ParasiteChemotherapy,SwissTropicalInstitute,Basel,Switzerland Abstract Background:HumanAfricantrypanosomiasis(HAT),amajorparasiticdiseasespreadinAfrica,urgentlyneedsnoveltargets and new efficacious chemotherapeutic agents. Recently, we discovered that 4-[5-(4-phenoxyphenyl)-2H-pyrazol-3- yl]morpholine (compound 1) exhibits specific antitrypanosomal activity with an IC50 of 1.0mM on Trypanosoma brucei rhodesiense(T.b.rhodesiense),thecausativeagentoftheacuteformofHAT. Methodology/PrincipalFindings:InthisworkweshowadenosinekinaseofT.b.rhodesiense(TbrAK),akeyenzymeofthe parasitepurinesalvagepathwaywhichisvitalforparasitesurvival,tobetheputativeintracellulartargetofcompound1 usingachemicalproteomicsapproach.ThisfindingwasconfirmedbyRNAinterferenceexperimentsshowingthatdown- regulationofadenosinekinasecounteractscompound1activity.Furtherchemicalvalidationdemonstratedthatcompound 1 interacts specifically and tightly with TbrAK with nanomolar affinity, and in vitro activity measurements showed that compound1isanenhancerofTbrAKactivity.Thesubsequentkineticanalysisprovidedstrongevidencethattheobserved hyperactivationofTbrAKisduetotheabolishmentoftheintrinsicsubstrate-inhibition. Conclusions/Significance:TheresultssuggestthatTbrAKistheputativetargetofthiscompound,andthathyperactivation ofTbrAKmayrepresentanoveltherapeuticstrategyforthedevelopmentoftrypanocides. Citation: Kuettel S, Mosimann M, Ma¨ser P, Kaiser M, Brun R, et al. (2009) Adenosine Kinase of T. b. rhodesiense Identified as the Putative Target of 4-[5-(4- phenoxyphenyl)-2H-pyrazol-3-yl]morpholineUs