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

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.