ArticleCell chemical biology2016
Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites.
Article in Cell chemical biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- IPMK at the crossroads of cellular signaling in health and disease.FEBS letters · 2026Review
- Enzyme Assays for Phosphoinositide Kinases and Phosphatases and Inhibitor Screens.Methods in molecular biology (Clifton, N.J.) · 2026Article
- Chromosome compartment assembly is essential for subtelomeric gene silencing in trypanosomes.Nature communications · 2025Article
- From Obscurity to Prominence: IPMK's Expanding Role in Cellular Signaling, Physiology, and Disease.Biomolecules · 2025Review
- Deep mutational scanning of the RNase III-like domain inFrontiers in cellular and infection microbiology · 2024Article
- In Silico Identification and Analysis of Proteins Containing the Phox Homology Phosphoinositide-Binding Domain in Kinetoplastea Protists: Evolutionary Conservation and Uniqueness of Phox-Homology-Domain-Containing Protein Architectures.International journal of molecular sciences · 2023Article
- Development of a 2,4-Diaminothiazole Series for the Treatment of Human African Trypanosomiasis Highlights the Importance of Static-Cidal Screening of Analogues.Journal of medicinal chemistry · 2023Article
- Genome-Wide Libraries for Protozoan Pathogen Drug Target Screening Using Yeast Surface Display.ACS infectious diseases · 2023Article
- Identification of Inhibitors of theACS medicinal chemistry letters · 2022Article
- Spatial metabolomics identifies localized chemical changes in heart tissue during chronic cardiac Chagas Disease.PLoS neglected tropical diseases · 2021Article
- Inositol polyphosphate-protein interactions: Implications for microbial pathogenicity.Cellular microbiology · 2021Review
- The Inositol Pyrophosphate Biosynthetic Pathway ofACS chemical biology · 2021Article
- The phosphoinositide regulatory network in Trypanosoma brucei: Implications for cell-wide regulation in eukaryotes.PLoS neglected tropical diseases · 2020Review
- Phosphoinositide signaling and regulation in Trypanosoma brucei: Specialized functions in a protozoan pathogen.PLoS pathogens · 2020Review
- Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics.Scientific reports · 2019Article
- Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure-Activity Analysis.Journal of medicinal chemistry · 2019Article
- Signaling through non-membrane nuclear phosphoinositide binding proteins in human health and disease.Journal of lipid research · 2019Review
- Nuclear Phosphatidylinositol 5-Phosphatase Is Essential for Allelic Exclusion of Variant Surface Glycoprotein Genes in Trypanosomes.Molecular and cellular biology · 2019Article
- Inositol phosphate kinases: Expanding the biological significance of the universal core of the protein kinase fold.Advances in biological regulation · 2019Review
- Inositol polyphosphate multikinase regulation of Trypanosoma brucei life stage development.Molecular biology of the cell · 2018Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.