ArticleChemistry & biology2015
Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and Growth in Trypanosoma brucei.
Article in Chemistry & biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- Druggable Sterol Metabolizing Enzymes in Infectious Diseases: Cell Targets to Therapeutic Leads.Biomolecules · 2024Review
- Polyamine Metabolism for Drug Intervention in Trypanosomatids.Pathogens (Basel, Switzerland) · 2024Review
- Steroidal Antimetabolites Protect Mice againstMolecules (Basel, Switzerland) · 2022Article
- Lipid and fatty acid metabolism in trypanosomatids.Microbial cell (Graz, Austria) · 2021Review
- Inhibition of Phytosterol Biosynthesis by Azasterols.Molecules (Basel, Switzerland) · 2020Article
- Anti-parasitic drug discovery takes a giant leap forward.Journal of lipid research · 2019Article
- Steroidal antibiotics are antimetabolites of Acanthamoeba steroidogenesis with phylogenetic implications.Journal of lipid research · 2019Article
- Microbial Sterolomics as a Chemical Biology Tool.Molecules (Basel, Switzerland) · 2018Review
- Synthesis and Biological Activity of Sterol 14α-Demethylase and Sterol C24-Methyltransferase Inhibitors.Molecules (Basel, Switzerland) · 2018Review
- Sterol methyltransferase a target for anti-amoeba therapy: towards transition state analog and suicide substrate drug design.Journal of lipid research · 2017Article
- Lipidomics and anti-trypanosomatid chemotherapy.Clinical and translational medicine · 2017Review
- Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model.PLoS neglected tropical diseases · 2016Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Trypanosoma brucei, the causal agent for sleeping sickness, depends on ergosterol for growth. Here, we describe the effects of a mechanism-based inhibitor, 26-fluorolanosterol (26FL), which converts in vivo to a fluorinated substrate of the sterol C24-methyltransferase essential for sterol methylation and function of ergosterol, and missing from the human host. 26FL showed potent inhibition of ergosterol biosynthesis and growth of procyclic and bloodstream forms while having no effect on cholesterol biosynthesis or growth of human epithelial kidney cells. During exposure of cloned TbSMT to 26-fluorocholesta-5,7,24-trienol, the enzyme is gradually killed as a consequence of the covalent binding of the intermediate C25 cation to the active site (kcat/kinact = 0.26 min(-1)/0.24 min(-1); partition ratio of 1.08), whereas 26FL is non-productively bound. These results demonstrate that poisoning of ergosterol biosynthesis by a 26-fluorinated Δ(24)-sterol is a promising strategy for developing a new treatment for trypanosomiasis.
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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.