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 (IC(50) value: 1 nM) to eliminate trypanosomes in human infective strain cultures.
Nakamura
Kosuke
K
Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Tokyo 113-0033, Japan. kosnakamura@nihs.go.jp
Fujioka
Sunao
S
Fukumoto
Shinya
S
Inoue
Noboru
N
Sakamoto
Kimitoshi
K
Hirata
Haruyuki
H
Kido
Yasutoshi
Y
Yabu
Yoshisada
Y
Suzuki
Takashi
T
Watanabe
Yoh-ichi
Y
Saimoto
Hiroyuki
H
Akiyama
Hiroshi
H
Kita
Kiyoshi
K
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
D004791:Enzyme Inhibitors; D024101:Mitochondrial Proteins; D010088:Oxidoreductases; D010940:Plant Proteins; D015800:Protozoan Proteins; D012717:Sesquiterpenes; D000099188:Alternative Oxidase; C006640:ascofuranone