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Chemogenetic characterization of inositol phosphate metabolic pathway reveals druggable enzymes for targeting kinetoplastid parasites

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Date
2016
Author
Cestari, Igor
Haas, Paige
Moretti, Nilmar Silvio [UNIFESP]
Schenkman, Sergio [UNIFESP]
Stuart, Ken
Type
Artigo
Is part of
Cell Chemical Biology
DOI
http://dx.doi.org/10.1016/j.chembiol.2016.03.015
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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.
Keywords
T brucei
T cruzi
Inositol
Drug discovery
Sponsorship
Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
URI
https://repositorio.unifesp.br/xmlui/handle/11600/62322
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  • EPM - Artigos [16058]

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