Dataset Information

Screening and Identification of Inhibitors of Trypanosoma brucei Cathepsin L with Antitrypanosomal Activity.

ABSTRACT: Current treatment options for human African trypanosomiasis (HAT) are ineffective, and they have several well-known clinical limitations. In our continued efforts to identify chemotypes that can be developed into clinically useful drugs, we screened a targeted compound library against the major cathepsin L (rhodesain) in T. brucei. We report the antirhodesain activity and antitrypanosomal activity of the compounds in this letter. The identified compounds can serve as starting points for structure- and/or phenotype-based lead optimization strategy against Trypanosoma brucei.

SUBMITTER: Jefferson T

PROVIDER: S-EPMC4715686 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Screening and Identification of Inhibitors of Trypanosoma brucei Cathepsin L with Antitrypanosomal Activity.

Jefferson Tierra T McShan Danielle D Warfield Jasmine J Ogungbe Ifedayo Victor IV

Chemical biology & drug design 20150827 1

Current treatment options for human African trypanosomiasis (HAT) are ineffective, and they have several well-known clinical limitations. In our continued efforts to identify chemotypes that can be developed into clinically useful drugs, we screened a targeted compound library against the major cathepsin L (rhodesain) in T. brucei. We report the antirhodesain activity and antitrypanosomal activity of the compounds in this letter. The identified compounds can serve as starting points for structur ...[more]

PMID: 26242248

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Project description:We reported recently that administration of ([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811), an enzyme-activated irreversible inhibitor of S-adenosyl-L-methionine decarboxylase (AdoMetDC; EC 4.1.1.50), a key enzyme in the synthesis of spermidine, cures African trypanosome infections in mice. The precise mechanism of action of MDL 73811 was not clear because a rapid disappearance of trypanosomes from the bloodstream of treated rats occurred before significant depletion of spermidine. Administration of MDL 73811 to Trypanosoma brucei brucei-infected rats resulted in a 70% decrease in parasitaemia within 1 h and a complete disappearance of parasites by 5 h. The reduction in parasitaemia was accompanied by complete inhibition of AdoMetDC activity by 10 min after injection of MDL 73811; inhibition was sustained for at least 4 h. Polyamine levels in trypanosomes were unaffected during the first 1 h in which the marked decrease in parasitaemia was observed, but parasite AdoMet levels increased 20-fold within this time. In contrast, exposure of cultured mammalian cells to MDL 73811 resulted in only a 1.5-2-fold increase in AdoMet levels over a 6 h time course. Experiments with inhibitors of ornithine decarboxylase (ODC) also suggested that the increased AdoMet levels might be an important factor for antitrypanosomal efficacy. Trypanosomes taken from rats treated for 36 h with eflornithine, an inhibitor of ODC, were depleted of putrescine and had markedly decreased spermidine levels. These organisms also had less than 10% of control AdoMetDC activity, and had elevated decarboxy AdoMet (greater than 4000-fold) and AdoMet (up to 50-fold) levels. The methyl ester of alpha-monofluromethyl-3,4-dehydro-ornithine (delta-MFMO-CH3), which cures murine T. b. brucei infections, and the ethyl ester analogue of this compound (delta-MFMO-C2H5), which does not cure this infection, become ODC inhibitors upon hydrolysis and thus were tested for their effects on trypanosomal polyamines, AdoMet and decarboxy AdoMet levels. Although both esters of delta-MFMO depleted trypanosomal polyamines, AdoMet and decarboxy AdoMet levels were elevated in T. b. brucei from infected mice treated with delta-MFMO-CH3 but not in parasites from mice treated with the delta-MFMO-C2H5. These data suggest that inhibition of AdoMetDC, either directly with MDL 73811 or indirectly with inhibitors of ODC, apparently leads to a trypanosome-specific elevation of AdoMet. It is possible that major changes in AdoMet, rather than changes in polyamines, may be responsible for the antitrypanosomal effects of these drugs.

Dataset Information

Screening and Identification of Inhibitors of Trypanosoma brucei Cathepsin L with Antitrypanosomal Activity.

Publications

Screening and Identification of Inhibitors of Trypanosoma brucei Cathepsin L with Antitrypanosomal Activity.

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