Antimalarial effects of vinyl sulfone cysteine proteinase inhibitors

Abstract

We evaluated the antimalarial effects of vinyl sulfone cysteine proteinase inhibitors. A number of vinyl sulfones strongly inhibited falcipain, a Plasmodium falciparum cysteine proteinase that is a critical hemoglobinase. In studies of cultured parasites, nanomolar concentrations of three vinyl sulfones inhibited parasite hemoglobin degradation, metabolic activity, and development. The antimalarial effects correlated with the inhibition of falcipain. Our results suggest that vinyl sulfones or related cysteine proteinase inhibitors may have promise as antimalarial agents.

Antiplasmodial activity of extracts from seven medicinal plants used in malaria treatment in Cameroon

“…Activity was measured as hydrolysis of the fluorogenic substrate benzyloxycarbonyl-Leu-Arg-7-amino-4-methyl-coumarin (Z-LeuArg-AMC) by using microplate reactions and a Fluoroskan II spectrofluorometer, as described previously (Rosenthal et al, 1996). For inhibitor assays, recombinant falcipain-2 prepared as described previously (Shenai et al, 2000) was incubated with inhibitors (added from stocks concentrated 100-to 1000-fold in dimethyl sulfoxide [DMSO]) with 10 mM dithiothreitol, pH 5.5, for 30 min at room temperature before the substrate (50 M) was added.…”

Novel molecular targets for antimalarial chemotherapy

“…Examples include fluoromethyl ketones, vinyl sulfones and chalcones, which target the cysteine proteases [16,17]. The statine, allophenylnorstatine and diphenylurea derivatives target the aspartic proteases [18].…”

Evaluation of cysteine proteases of Plasmodium vivax as antimalarial drug targets: sequence analysis and sensitivity to cysteine protease inhibitors

“…Activity was measured as hydrolysis of the fluorogenic substrate benzyloxycarbonyl-Leu-Arg-7-amino-4-methylcoumarin (Z-Leu-Arg-AMC) in microplate reactions, as described previously (Rosenthal et al 1996). For inhibition assays, recombinant enzymes were incubated with inhibitors with 10 mM dithiothreitol (DTT), pH 5.5, for 30 min at room temperature before adding the substrate.…”