dc.contributor | http://lattes.cnpq.br/2131472726202687 | |
dc.creator | Cestari, Igor | |
dc.creator | Haas, Paige | |
dc.creator | Moretti, Nilmar Silvio [UNIFESP] | |
dc.creator | Schenkman, Sergio [UNIFESP] | |
dc.creator | Stuart, Ken | |
dc.date.accessioned | 2021-11-29T13:09:43Z | |
dc.date.accessioned | 2023-09-04T18:26:00Z | |
dc.date.available | 2021-11-29T13:09:43Z | |
dc.date.available | 2023-09-04T18:26:00Z | |
dc.date.created | 2021-11-29T13:09:43Z | |
dc.date.issued | 2016 | |
dc.identifier | https://repositorio.unifesp.br/xmlui/handle/11600/62322 | |
dc.identifier | http://dx.doi.org/10.1016/j.chembiol.2016.03.015 | |
dc.identifier.uri | https://repositorioslatinoamericanos.uchile.cl/handle/2250/8614581 | |
dc.description.abstract | Kinetoplastids 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.publisher | Cell Press | |
dc.relation | Cell Chemical Biology | |
dc.rights | Acesso aberto | |
dc.subject | T brucei | |
dc.subject | T cruzi | |
dc.subject | Inositol | |
dc.subject | Drug discovery | |
dc.title | Chemogenetic characterization of inositol phosphate metabolic pathway reveals druggable enzymes for targeting kinetoplastid parasites | |
dc.type | Artigo | |