Trypanosome alternative oxidase, a potential therapeutic target for sleeping sickness, is conserved among Trypanosoma brucei subspecies

Trypanosoma brucei rhodesiense and T. b. gambiense are known causes of human African trypanosomiasis (HAT), or “sleeping sickness,” which is deadly if untreated. We previously reported that a specific inhibitor of trypanosome alternative oxidase (TAO), ascofuranone, quickly kills African trypanosomes in vitro and cures mice infected with another subspecies, non-human infective T. b. brucei, in in vivo trials. As an essential factor for trypanosome survival, TAO is a promising drug target due to the absence of alternative oxidases in the mammalian host. This study found TAO expression in HAT-causing trypanosomes; its amino acid sequence was identical to that in non-human infective T. b. brucei. The biochemical understanding of the TAO including its 3 dimensional structure and inhibitory compounds against TAO could therefore be applied to all three T. brucei subspecies in search of a cure for HAT. Our in vitro study using T. b. rhodesiense confirmed the effectiveness of ascofuranone (IC50 value: 1 nM) to eliminate trypanosomes in human infective strain cultures.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideResearch Highlights►TAO amino acid sequence was identical among T. brucei subspecies. ►Efficacy of TAO inhibitor extends to the human infective T. brucei subspecies. ►In vitro study using T. b. rhodesiense indicated that ascofuranone was effective to eliminate trypanosomes in human infective strain culture.