Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites

Author(s)

Cestari, Igor ; Haas, Paige ; Moretti, Nilmar Silvio ; Schenkman, Sergio ; Stuart, Ken

• Document type: Journal article
• Source: Cell Chemical Biology; v. 23, n. 5, p. 608-617, MAY 19 2016.
• Web of Science Citations: 7

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. (AU)

• FAPESP's process: 13/20074-9 - Global analysis of protein acetylation in Trypanosoma cruzi
• Grantee: Nilmar Silvio Moretti
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 11/51973-3 - Cell signaling mechanism of Trypanosoma in response to nutritional alterations and genotoxic agents
• Grantee: Sergio Schenkman
• Support Opportunities: Research Projects - Thematic Grants