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dc.contributor.authorCestari, Igor
dc.contributor.authorHaas, Paige
dc.contributor.authorMoretti, Nilmar Silvio [UNIFESP]
dc.contributor.authorSchenkman, Sergio [UNIFESP]
dc.contributor.authorStuart, Ken
dc.date.accessioned2021-11-29T13:09:43Z
dc.date.available2021-11-29T13:09:43Z
dc.date.issued2016
dc.identifier.urihttps://repositorio.unifesp.br/xmlui/handle/11600/62322
dc.description.abstractKinetoplastids cause Chagas disease, human Afri- can trypanosomiasis, and leishmaniases. Current treatments for these diseases are toxic and ineffi- cient, and our limited knowledge of drug targets and inhibitors has dramatically hindered the devel- opment of new drugs. Here we used a chemogenetic approach to identify new kinetoplastid drug targets and inhibitors. We conditionally knocked down Try- panosoma brucei inositol phosphate (IP) pathway genes and showed that almost every pathway step is essential for parasite growth and infection. Using a genetic and chemical screen, we identified inhibi- tors that target IP pathway enzymes and are selec- tive against T. brucei. Two series of these inhibitors acted on T. brucei inositol polyphosphate multiki- nase (IPMK) preventing Ins(1,4,5)P3 and Ins(1,3,4,5) P4 phosphorylation. We show that IPMK is function- ally conserved among kinetoplastids and that its inhi- bition is also lethal for Trypanosoma cruzi. Hence, IP enzymes are viable drug targets in kinetoplastids, and IPMK inhibitors may aid the development of new drugs.pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.languageengpt_BR
dc.publisherCell Presspt_BR
dc.relation.ispartofCell Chemical Biologypt_BR
dc.rightsAcesso abertopt_BR
dc.subjectT bruceipt_BR
dc.subjectT cruzipt_BR
dc.subjectInositolpt_BR
dc.subjectDrug discoverypt_BR
dc.titleChemogenetic characterization of inositol phosphate metabolic pathway reveals druggable enzymes for targeting kinetoplastid parasitespt_BR
dc.typeArtigopt_BR
dc.description.sponsorshipIDFAPESP: 2012/09403-8; 2013/20074-9pt_BR
dc.identifier.doihttp://dx.doi.org/10.1016/j.chembiol.2016.03.015pt_BR
unifesp.campusEscola Paulista de Medicina (EPM)pt_BR
unifesp.graduateProgramMicrobiologia e Imunologiapt_BR
unifesp.knowledgeAreaOutrapt_BR
dc.contributor.authorLatteshttp://lattes.cnpq.br/2131472726202687pt_BR
unifesp.departamentoMicrobiologia, Imunologia e Parasitologiapt_BR


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