A structural analog, 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxy
adenosine (
MDL 73811), of decarboxy
S-adenosyl-L-methionine, the product of the reaction catalyzed by
S-adenosyl-L-methionine (
AdoMet)
decarboxylase (DC), was found to inhibit Trypanosoma brucei brucei
AdoMet DC. The inhibition was time dependent (tau 50, 0.3 min), exhibited pseudo-first-order kinetics (Ki, 1.5 microM), and was apparently irreversible. The natural substrate of the reaction,
AdoMet, protected the
enzyme from inactivation, suggesting that
MDL 73811 was directed at the
enzyme active site and was probably catalytically activated. Administration of
MDL 73811 to T. b. brucei-infected rats resulted in rapid inhibition of
AdoMet DC activity, a decrease in
spermidine, and an increase in
putrescine in the trypanosomes isolated from treated rats. Treatment of T. b. brucei-infected mice with
MDL 73811 (20 mg/kg of
body weight intraperitoneally twice daily for 4 days) resulted in cures of the trypanosome
infections. Additionally,
drug-resistant T. brucei rhodesiense
infections in mice were cured by either a combination of
MDL 73811 (50 mg/kg intraperitoneally three times per day for 5 days) and relatively low oral doses of
alpha-difluoromethylornithine or
MDL 73811 (50 mg/kg per day for 7 days) administered alone in implanted miniosmotic pumps. These data suggest that
MDL 73811 and, perhaps, other inhibitors of
AdoMet DC have potential for
therapeutic use in various forms of
African trypanosomiasis.