Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites. Issue 5 (19th May 2016)

• Record Type: Journal Article
• Authors: Cestari, Igor; Haas, Paige; Moretti, Nilmar Silvio; Schenkman, Sergio; Stuart, Ken
• Is Part Of: Cell chemical biology. Volume 23:Issue 5(2016)
• Page Start: 608
• Page End: 617
• Publication Date: 2016-05-19
• Subjects: Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2016.03.015
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Kinetoplastids cause Chagas disease, human African trypanosomiasis, and leishmaniases. Current treatments for these diseases are toxic and inefficient, and our limited knowledge of drug targets and inhibitors has dramatically hindered the development of new drugs. Here we used a chemogenetic approach to identify new kinetoplastid drug targets and inhibitors. We conditionally knocked down Trypanosoma 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 inhibitors that target IP pathway enzymes and are selective against T. brucei . Two series of these inhibitors acted on T. brucei inositol polyphosphate multikinase (IPMK) preventing Ins(1, 4, 5)P3 and Ins(1, 3, 4, 5)P4 phosphorylation. We show that IPMK is functionally conserved among kinetoplastids and that its inhibition 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. Graphical Abstract: Highlights: Inositol phosphate pathway genes are essential for T. brucei infection Chemical genetic screen used to identify inositol phosphate pathway inhibitors Two series of molecules inhibit Ins(1, 4, 5)P3 and Ins(1, 3, 4, 5)P4 phosphorylation Inhibitors are lethal to T. brucei and for T. cruzi intracellular amastigotes Abstract : Cestari et al. identified steps of the inositol phosphate pathway that are essential for Trypanosoma brucei infection. Using a chemical genetic approach they discovered small molecules that inhibit phosphorylation of Ins(1, 4, 5)P3 and Ins(1, 3, 4, 5)P4 and that are lethal to T. brucei and other related parasites.