Cysteine protease as a target for nitric oxide in parasitic organisms

Nitric oxide (NO) is an important cytotoxic and cytostatic mediator for several parasites, including intracellular (e.g. Trypanosoma, Leishmania, Plasmodium, Toxoplasma) and extracellular (e.g. Entamoeba) protozoa and the helminth Schistosoma. Increasing evidence suggests that parasitic cysteine proteases could represent NO targets, providing molecular bases for the parasiticidal effect of NO. NO-donors (e.g. S-nitroso-acetyl-penicillamine, SNAP) inhibitthe catalytic activity of cruzipain, falcipain and Leishmania infantarti cysteine protease in vitro. L. infantum cysteine protease is inhibited following incubation of promastigotes with SNAP, which leads to parasite killing. Although NO-mediated chemical modification(s) of cysteine proteases accounts for the loss of enzyme activity and the parasiticidal effect of NO, the binding of NO to other parasite molecular targets should be taken into account. In particular, ribonucleotide reductase inhibition has been suggested to explain the cytostatic effect of NO on Trypanosoma brucei gambiense and Trypanosoma bruceì brucei. Moreover, the NO-mediated chemical modification(s) of host cysteine-containing proteins could also influence parasite survival.Considering that cysteine proteases appear as promising targets for anti-parasite chemotherapy, NO-releasing drugs could have an enhancing role in thè therapeutic treatment of parasitic diseases.