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Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase. 1990

A J Bitonti, and T L Byers, and T L Bush, and P J Casara, and C J Bacchi, and A B Clarkson, and P P McCann, and A Sjoerdsma
Merrell Dow Research Institute, Cincinnati, Ohio 45215.

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.

UI MeSH Term Description Entries
D003839 Deoxyadenosines Adenosine molecules which can be substituted in any position, but are lacking one hydroxyl group in the ribose part of the molecule. Adenine Deoxyribonucleosides,Adenylyldeoxyribonucleosides,Deoxyadenosine Derivatives,Deoxyribonucleosides, Adenine,Derivatives, Deoxyadenosine
D004352 Drug Resistance, Microbial The ability of microorganisms, especially bacteria, to resist or to become tolerant to chemotherapeutic agents, antimicrobial agents, or antibiotics. This resistance may be acquired through gene mutation or foreign DNA in transmissible plasmids (R FACTORS). Antibiotic Resistance,Antibiotic Resistance, Microbial,Antimicrobial Resistance, Drug,Antimicrobial Drug Resistance,Antimicrobial Drug Resistances,Antimicrobial Resistances, Drug,Drug Antimicrobial Resistance,Drug Antimicrobial Resistances,Drug Resistances, Microbial,Resistance, Antibiotic,Resistance, Drug Antimicrobial,Resistances, Drug Antimicrobial
D000518 Eflornithine An inhibitor of ORNITHINE DECARBOXYLASE, the rate limiting enzyme of the polyamine biosynthetic pathway. Difluoromethylornithine,alpha-Difluoromethylornithine,DL-alpha-Difluoromethylornithine,Eflornithine Hydrochloride,Eflornithine Monohydrochloride, Monohydrate,MDL-71,782 A,Ornidyl,RMI 71782,Vaniqa,alpha-Difluoromethyl Ornithine,DL alpha Difluoromethylornithine,MDL 71,782 A,MDL71,782 A,Ornithine, alpha-Difluoromethyl,alpha Difluoromethyl Ornithine,alpha Difluoromethylornithine
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012437 Adenosylmethionine Decarboxylase An enzyme that catalyzes the decarboxylation of S-adenosyl-L-methionine to yield 5'-deoxy-(5'-),3-aminopropyl-(1), methylsulfonium salt. It is one of the enzymes responsible for the synthesis of spermidine from putrescine. EC 4.1.1.50. S-Adenosylmethionine Decarboxylase,Decarboxylase, Adenosylmethionine,Decarboxylase, S-Adenosylmethionine,S Adenosylmethionine Decarboxylase
D014346 Trypanosoma brucei brucei A hemoflagellate subspecies of parasitic protozoa that causes nagana in domestic and game animals in Africa. It apparently does not infect humans. It is transmitted by bites of tsetse flies (Glossina). Trypanosoma brucei,Trypanosoma brucei bruceus,Trypanosoma bruceus,brucei brucei, Trypanosoma,brucei, Trypanosoma brucei,bruceus, Trypanosoma,bruceus, Trypanosoma brucei
D014353 Trypanosomiasis, African A disease endemic among people and animals in Central Africa. It is caused by various species of trypanosomes, particularly T. gambiense and T. rhodesiense. Its second host is the TSETSE FLY. Involvement of the central nervous system produces "African sleeping sickness." Nagana is a rapidly fatal trypanosomiasis of horses and other animals. African Sleeping Sickness,Nagana,African Trypanosomiasis,African Sleeping Sicknesses,African Trypanosomiases,Sickness, African Sleeping,Sicknesses, African Sleeping,Sleeping Sickness, African,Sleeping Sicknesses, African,Trypanosomiases, African
D015317 Biogenic Polyamines Biogenic amines having more than one amine group. These are long-chain aliphatic compounds that contain multiple amino and/or imino groups. Because of the linear arrangement of positive charge on these molecules, polyamines bind electrostatically to ribosomes, DNA, and RNA. Polyamines, Biogenic
D051379 Mice The common name for the genus Mus. Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus

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