title: Trypanosome alternative oxidase, a potential therapeutic target for sleeping sickness, is conserved among Trypanosoma brucei subspecies.
abstract: 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 (IC(50) value: 1 nM) to eliminate trypanosomes in human infective strain cultures.
authors.affiliation: Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Tokyo 113-0033, Japan. kosnakamura@nihs.go.jp
authors.forename: Kosuke
authors.initials: K
authors.lastname: Nakamura
authors.forename: Sunao
authors.initials: S
authors.lastname: Fujioka
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Noboru
authors.initials: N
authors.lastname: Inoue
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Hirata
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Kido
authors.forename: Yoshisada
authors.initials: Y
authors.lastname: Yabu
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Yoh-ichi
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akiyama
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kita
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017124:Conserved Sequence; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010940:Plant Proteins; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D012717:Sesquiterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000145:classification* / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D014347:Trypanosoma brucei gambiense / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D014353:Trypanosomiasis, African / Q000188:drug therapy / Q000469:parasitology*; D000099188:Alternative Oxidase
chemical_list: D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D015800:Protozoan Proteins; D012717:Sesquiterpenes; D000099188:Alternative Oxidase; C006640:ascofuranone