Download MendeleyUncovering the Unusual Inhibition Mechanism of a Trypanosome Alternative Oxidase Inhibitor Displaying Broad-Spectrum Activity against African Animal Trypanosomes.
Ebiloma, G.U., Balogun, E.O., Arai, N., Otani, M., Baldassarri, C., Alhejely, A., Cueto-Diaz, E., De Koning, H.P., Dardonville, C., Shiba, T.(2025) J Med Chem 68: 17155-17174
- PubMed: 40464345
- DOI: https://doi.org/10.1021/acs.jmedchem.5c00631
- Primary Citation of Related Structures:
9KUN, 9M2A - PubMed Abstract:
The glucose-dependent respiration of bloodstream forms of the parasite Trypanosoma brucei depends on an unusual and essential mitochondrial electron-transport system, consisting of glycerol-3-phosphate dehydrogenase and the trypanosome alternative oxidase (TAO). We report here the discovery of an allosteric inhibitor of TAO that displays highly potent activity (EC 50 values in the range 1-20 nM) against the important veterinary pathogens T. b. brucei , Trypanosoma evansi , Trypanosoma equiperdum , and Trypanosoma congolense , i.e., >5-fold greater potency than the standard drugs. The methylene-linked 2-methyl-4-hydroxybenzoate 2-pyridinyldiphenylphosphonium derivative ( 1 ) was the best inhibitor of recombinant TAO (IC 50 = 1.3 nM) via a noncompetitive/allosteric mechanism ( K i = 3.46 nM). Remarkably, X-ray crystallography showed that 1 was bound to a site of TAO ∼25 Å from the catalytic pocket. Although 1 demonstrated good safety toward mammalian cells in vitro (selectivity index >2300), it did not fully clear parasitemia in experimental animals, attributable to a high hepatic clearance.
- School of Science, Engineering & Environment, University of Salford, Manchester M5 4NT, United Kingdom.
Organizational Affiliation:
