ArticlePLoS neglected tropical diseases2017
Photo-affinity labelling and biochemical analyses identify the target of trypanocidal simplified natural product analogues.
Article in PLoS neglected tropical diseases, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 33 citations in OpenAlex.
- Azidocoumarin Glycan Probes for Photoinduced Cross-Linking and In Situ Fluorescent Labeling.Bioconjugate chemistry · 2026Article
- Mass Spectrometry Proteomics: A Key to Faster Drug Discovery.Journal of medicinal chemistry · 2026Review
- Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Potential Trypanocidal Activity of Glycerol Analogues.ChemistryOpen · 2024Article
- Evaluation of Antibacterial Functionalized Dihydropyrimidine Photoaffinity Probes Toward Mechanism of Action Studies.ACS medicinal chemistry letters · 2024Article
- Characterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazole.Microbiology spectrum · 2024Article
- Target identification of small molecules: an overview of the current applications in drug discovery.BMC biotechnology · 2023Review
- Structure-function relationships in aryl diazirines reveal optimal design features to maximize C-H insertion.Chemical science · 2021Article
- Photoaffinity labelling strategies for mapping the small molecule-protein interactome.Organic & biomolecular chemistry · 2021Review
- How Physiologic Targets Can Be Distinguished from Drug-Binding Proteins.Molecular pharmacology · 2021Article
- Experimental Strategies to Explore Drug Action and Resistance in Kinetoplastid Parasites.Microorganisms · 2020Review
- Structure-Based Design, Synthesis and Biological Evaluation of Bis-Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase.European journal of organic chemistry · 2019Article
- Branched late-steps of the cytosolic iron-sulphur cluster assembly machinery of Trypanosoma brucei.PLoS pathogens · 2018Article
- A fixable probe for visualizing flagella and plasma membranes of the African trypanosome.PloS one · 2018Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Current drugs to treat African sleeping sickness are inadequate and new therapies are urgently required. As part of a medicinal chemistry programme based upon the simplification of acetogenin-type ether scaffolds, we previously reported the promising trypanocidal activity of compound 1, a bis-tetrahydropyran 1,4-triazole (B-THP-T) inhibitor. This study aims to identify the protein target(s) of this class of compound in Trypanosoma brucei to understand its mode of action and aid further structural optimisation. We used compound 3, a diazirine- and alkyne-containing bi-functional photo-affinity probe analogue of our lead B-THP-T, compound 1, to identify potential targets of our lead compound in the procyclic form T. brucei. Bi-functional compound 3 was UV cross-linked to its target(s) in vivo and biotin affinity or Cy5.5 reporter tags were subsequently appended by Cu(II)-catalysed azide-alkyne cycloaddition. The biotinylated protein adducts were isolated with streptavidin affinity beads and subsequent LC-MSMS identified the FoF1-ATP synthase (mitochondrial complex V) as a potential target. This target identification was confirmed using various different approaches. We show that (i) compound 1 decreases cellular ATP levels (ii) by inhibiting oxidative phosphorylation (iii) at the FoF1-ATP synthase. Furthermore, the use of GFP-PTP-tagged subunits of the FoF1-ATP synthase, shows that our compounds bind specifically to both the α- and β-subunits of the ATP synthase. The FoF1-ATP synthase is a target of our simplified acetogenin-type analogues. This mitochondrial complex is essential in both procyclic and bloodstream forms of T. brucei and its identification as our target will enable further inhibitor optimisation towards future drug discovery. Furthermore, the photo-affinity labeling technique described here can be readily applied to other drugs of unknown targets to identify their modes of action and facilitate more broadly therapeutic drug design in any pathogen or disease model.
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