Fluorinated Sterols Are Suicide Inhibitors of Ergosterol Biosynthesis and Growth in Trypanosoma brucei. Issue 10 (22nd October 2015) - Leaver, David J.
Summary: 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 Tb SMT 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 ( k cat / k inact = 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. Graphical Abstract: Highlights: Target-specific fluorinated drug effect on Trypanosoma brucei PCF and BSF growth 26-Fluorinated Δ 24 -sterol is a mechanism-based poison of ergosterol biosynthesis In vivo the Tb sterol C24-methyltransferase is inactivated by 26-fluorinated sterols Chemical and kinetic evaluation of 26-fluorinated steroids as suicide substrates Abstract : Leaver et al. used fluorinated steroids as suicide inhibitors of sterol C24 methyltransferase to inhibit ergosterol biosynthesis and growth of Trypanosoma brucei . This study demonstrates the potential of treating neglected tropical diseases with fluorinated analogs of a crucial enzyme in protozoan parasites absent from the human host.