dc.contributorhttp://lattes.cnpq.br/2131472726202687
dc.creatorCestari, Igor
dc.creatorHaas, Paige
dc.creatorMoretti, Nilmar Silvio [UNIFESP]
dc.creatorSchenkman, Sergio [UNIFESP]
dc.creatorStuart, Ken
dc.date.accessioned2021-11-29T13:09:43Z
dc.date.accessioned2023-09-04T18:26:00Z
dc.date.available2021-11-29T13:09:43Z
dc.date.available2023-09-04T18:26:00Z
dc.date.created2021-11-29T13:09:43Z
dc.date.issued2016
dc.identifierhttps://repositorio.unifesp.br/xmlui/handle/11600/62322
dc.identifierhttp://dx.doi.org/10.1016/j.chembiol.2016.03.015
dc.identifier.urihttps://repositorioslatinoamericanos.uchile.cl/handle/2250/8614581
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.
dc.publisherCell Press
dc.relationCell Chemical Biology
dc.rightsAcesso aberto
dc.subjectT brucei
dc.subjectT cruzi
dc.subjectInositol
dc.subjectDrug discovery
dc.titleChemogenetic characterization of inositol phosphate metabolic pathway reveals druggable enzymes for targeting kinetoplastid parasites
dc.typeArtigo


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