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The trypanocidal effect of NO-releasing agents is not due to inhibition of the major cysteine proteinase in Trypanosoma brucei

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Abstract

The lysosomal cysteine proteinase activity of bloodstream forms of Trypanosoma brucei is a validated drug target. Previously, it was reported that nitric oxide (NO)-releasing agents inhibit the catalytic activity of cysteine proteinases of the protozoan parasites Leishmania infantum, Trypanosoma cruzi and Plasmodium falciparum. In this study, we investigated the effect of the NO-donors S-nitrosoglutathione, (±)-(E)-4-ethyl-2[(E)-hydroxyimino]-5-nitro-3-hexenamide, 3-morpholinosydnonimine (SIN-1) and S-nitroso-N-acetyl-dl-penicillamine on the activity of the cysteine proteinase of T. brucei. At a concentration of 1 mM, the NO donors inhibited the catalytic activity of purified T. brucei cysteine proteinase by 50–90%. With the exception of SIN-1, all NO donors displayed trypanocidal activities against bloodstream forms of T. brucei in vitro with 50% growth inhibition values of around 30 μM. However, the NO donors were ineffective in significantly inhibiting the cysteine proteinase activity within the parasites. This finding was confirmed by the ineffectiveness of the NO donors to block proteinolysis in the lysosome of the parasites. The results show that the trypanocidal activity of NO donors cannot be attributed to the inhibition of the major lysosomal cysteine proteinase in bloodstream forms of T. brucei.

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Acknowledgements

We thank Dr Conor Caffrey for rhodesain. This work was supported by the John & Pamela Salter Charitable Trust (RCN.298317).

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  1. BioMedical Research Centre, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK

    Dietmar Steverding, Xia Wang & Darren W. Sexton

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  1. Dietmar Steverding
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  2. Xia Wang
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  3. Darren W. Sexton
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Correspondence to Dietmar Steverding.

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Steverding, D., Wang, X. & Sexton, D.W. The trypanocidal effect of NO-releasing agents is not due to inhibition of the major cysteine proteinase in Trypanosoma brucei . Parasitol Res 105, 1333–1338 (2009). https://doi.org/10.1007/s00436-009-1559-x

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