title: Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites.
abstract: 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.
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Cestari
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109, USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Haas
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo 04023-062, Brazil.
authors.forename: Nilmar Silvio
authors.initials: NS
authors.lastname: Moretti
authors.affiliation: Departamento de Microbiologia, Imunologia e Parasitologia, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, São Paulo 04023-062, Brazil.
authors.forename: Sergio
authors.initials: S
authors.lastname: Schenkman
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109, USA; Department of Global Health, University of Washington, Seattle, WA 98195, USA. Electronic address: ken.stuart@cidresearch.org.
authors.forename: Ken
authors.initials: K
authors.lastname: Stuart
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D007295:Inositol Phosphates / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010271:Parasites / Q000187:drug effects* / Q000201:enzymology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D014407:Tumor Cells, Cultured
chemical_list: D007295:Inositol Phosphates; D047428:Protein Kinase Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); C434257:inositol polyphosphate multikinase