ArticleeLife2013
Hypothemycin, a fungal natural product, identifies therapeutic targets in Trypanosoma brucei [corrected].
Article in eLife, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 50 citations in OpenAlex.
- Nature-Inspired Pathogen and Cancer Protein Covalent Inhibitors: From Plants and Other Natural Sources to Drug Development.Pathogens (Basel, Switzerland) · 2025Review
- Potent kinase inhibitors from the Merck KGaA OGHL: Novel hits against Trypanosoma brucei with potential for repurposing.PLoS neglected tropical diseases · 2025Article
- Phenotypic and omics analyses of the SordariomycetesmSystems · 2025Article
- A Convergent Approach to Resorcinolic Macrolides to Expand Structural Diversity.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Efficient synthesis of (±)-de-Tetrahedron letters · 2024Article
- Improved deconvolution of natural products' protein targets using diagnostic ions from chemical proteomics linkers.Beilstein journal of organic chemistry · 2024Review
- Covalent Inhibitors for Neglected Diseases: An Exploration of Novel Therapeutic Options.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Divergent polo boxes in KKT2 bind KKT1 to initiate the kinetochore assembly cascade inMolecular biology of the cell · 2022Article
- Article
- Currently Available Strategies for Target Identification of Bioactive Natural Products.Frontiers in chemistry · 2021Review
- Characterization of unconventional kinetochore kinases KKT10 and KKT19 inJournal of cell science · 2020Article
- Pep5, a Fragment of Cyclin D2, Shows Antiparasitic Effects in Different Stages of theAntimicrobial agents and chemotherapy · 2019Article
- Identification of inhibitors of an unconventional Trypanosoma brucei kinetochore kinase.PloS one · 2019Article
- Genetically Validated Drug Targets in Leishmania: Current Knowledge and Future Prospects.ACS infectious diseases · 2018Review
- Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions.Journal of medicinal chemistry · 2017Article
- Targeting Non-Catalytic Cysteine Residues Through Structure-Guided Drug Discovery.Current topics in medicinal chemistry · 2017Review
- The unconventional kinetoplastid kinetochore: from discovery toward functional understanding.Biochemical Society transactions · 2016Review
- Chemical proteomics approaches for identifying the cellular targets of natural products.Natural product reports · 2016Review
- Kinases as druggable targets in trypanosomatid protozoan parasites.Chemical reviews · 2014Review
- A road map to evaluate the proteome-wide selectivity of covalent kinase inhibitors.Nature chemical biology · 2014Article
Corrections and comments
- Commented on by
- Erratum issued
Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Protein kinases are potentially attractive therapeutic targets for neglected parasitic diseases, including African trypanosomiasis caused by the protozoan, Trypanosoma brucei. How to prioritize T. brucei kinases and quantify their intracellular engagement by small-molecule inhibitors remain unsolved problems. Here, we combine chemoproteomics and RNA interference to interrogate trypanosome kinases bearing a Cys-Asp-Xaa-Gly motif (CDXG kinases). We discovered that hypothemycin, a fungal polyketide previously shown to covalently inactivate a subset of human CDXG kinases, kills T. brucei in culture and in infected mice. Quantitative chemoproteomic analysis with a hypothemycin-based probe revealed the relative sensitivity of endogenous CDXG kinases, including TbGSK3short and a previously uncharacterized kinase, TbCLK1. RNAi-mediated knockdown demonstrated that both kinases are essential, but only TbCLK1 is fully engaged by cytotoxic concentrations of hypothemycin in intact cells. Our study identifies TbCLK1 as a therapeutic target for African trypanosomiasis and establishes a new chemoproteomic tool for interrogating CDXG kinases in their native context. DOI:http://dx.doi.org/10.7554/eLife.00712.001.
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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.