Abstract
Gold compounds form a new class of promising metal-based drugs with a number of potential therapeutic applications, particularly in the fields of anticancer and antimicrobial treatments. Previous research revealed that a group of structurally diverse gold compounds cause conspicuous inhibition of the protease activities of the human proteasome. Given the pharmacological importance of protease inhibition, the present study further explored whether these gold compounds might inhibit a few other proteases that are accepted druggable targets for disease treatment. In particular, four distinct cysteine proteases were considered here: cathepsin B and L that play a primary role in tumor-cell invasion and metastasis; rhodesain, the major cathepsin L-like cysteine protease of Trypanosoma brucei rhodesiense and CPB2.8ΔCTE, a Leishmania mexicana mature cysteine protease. Based on the encouraging results obtained for some of the tested gold compounds on the two parasitic cysteine proteases, especially against CPB2.8ΔCTE, with IC50s in the micromolar range, we next evaluated whether those gold compounds might contrast effectively the growth of the respective protozoa and indeed important antiprotozoal properties were disclosed; on the other hand a certain lack of selectivity was highlighted. Also, no direct or clear correlation could be established between the in vitro antiprotozoal properties and the level of protease inhibition. The implications of these results are discussed in relation to possible pharmaceutical applications.
Keywords:
Cysteine proteases; Enzyme inhibition; Gold compounds; Parasitic protozoa.
MeSH terms
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Animals
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Antiprotozoal Agents / chemical synthesis
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Antiprotozoal Agents / pharmacology*
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Cathepsin B / antagonists & inhibitors
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Cathepsin B / chemistry
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Cathepsin L / antagonists & inhibitors
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Cathepsin L / chemistry
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Cell Line
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Cysteine Endopeptidases / chemistry*
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Cysteine Proteinase Inhibitors / chemical synthesis
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Cysteine Proteinase Inhibitors / pharmacology*
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Humans
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Inhibitory Concentration 50
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Leishmania infantum / drug effects
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Leishmania infantum / enzymology
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Leishmania infantum / growth & development
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / enzymology
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Mice
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Organogold Compounds / chemical synthesis
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Organogold Compounds / pharmacology*
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology
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Plasmodium falciparum / growth & development
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Proteasome Endopeptidase Complex / chemistry
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / chemistry
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Recombinant Proteins / chemistry
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Trypanosoma brucei brucei / drug effects
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Trypanosoma brucei brucei / enzymology
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Trypanosoma brucei brucei / growth & development
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Trypanosoma brucei rhodesiense / drug effects
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Trypanosoma brucei rhodesiense / enzymology
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Trypanosoma brucei rhodesiense / growth & development
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Trypanosoma cruzi / drug effects
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Trypanosoma cruzi / enzymology
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Trypanosoma cruzi / growth & development
Substances
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Antiprotozoal Agents
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Cysteine Proteinase Inhibitors
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Organogold Compounds
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Protozoan Proteins
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Recombinant Proteins
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Cysteine Endopeptidases
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rhodesain
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CTSB protein, human
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Cathepsin B
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CTSL protein, human
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Cathepsin L
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Proteasome Endopeptidase Complex