An anthelmintic compound, nafuredin, shows selective inhibition of complex I in helminth mitochondria.
Infections with parasitic helminths are important causes of morbidity and mortality worldwide. New drugs that are parasite specific and minimally toxic to the host are needed to counter these infections effectively. Here we report the finding of a previously unidentified compound, nafuredin, from Aspergillus niger. Nafuredin inhibits NADH-fumarate reductase (complexes I + II) activity, a unique anaerobic electron transport system in helminth mitochondria, at nM order. It competes for the quinone-binding site in complex I and shows high selective toxicity to the helminth enzyme. Moreover, nafuredin exerts anthelmintic activity against Haemonchus contortus in in vivo trials with sheep. Thus, our study indicates that mitochondrial complex I is a promising target for chemotherapy, and nafuredin is a potential lead compound as an anthelmintic isolated from microorganisms.
Omura
S
S
Research Center for Biological Function, The Kitasato Institute, Shirokane, Minato-ku, Tokyo 108-8642, Japan. omura-s@kitasato.or.jp
Miyadera
H
H
Ui
H
H
Shiomi
K
K
Yamaguchi
Y
Y
Masuma
R
R
Nagamitsu
T
T
Takano
D
D
Sunazuka
T
T
Harder
A
A
Kölbl
H
H
Namikoshi
M
M
Miyoshi
H
H
Sakamoto
K
K
Kita
K
K
D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017165:Ascaris suum / Q000187:drug effects / Q000201:enzymology; D001234:Aspergillus niger / Q000737:chemistry*; D004579:Electron Transport / Q000187:drug effects; D005243:Feces / Q000469:parasitology; D006188:Haemonchiasis / Q000188:drug therapy; D006189:Haemonchus / Q000187:drug effects* / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors; D011753:Pyrones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012756:Sheep / Q000469:parasitology; D013997:Time Factors; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
D000871:Anthelmintics; D011753:Pyrones; C423563:nafuredin; D014451:Ubiquinone; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C020155:fumarate reductase (NADH); C003304:rhodoquinone