Chagas disease is a tropical parasitic disease caused by the flagellate protozoan parasite Trypanosoma cruzi. Treatment agents for the acute form of the disease are highly toxic, and there are no known effective medications for the chronic stage. Cruzipain is the primary cysteine protease involved in immune evasion and cell invasion of T. cruzi, and is essential in the life cycle of the parasite. Cruzipain inhibitors have been effective in eliminating the parasite from infected mice. This makes the protease an effective and validated target for future therapeutic agents.As part of a collaborative project between the Trawick and Pinney Laboratories at Baylor University, a focused library of non-peptidic small-molecule compounds containing a thiosemicarbazone moiety have been synthesized and screened as potent inhibitors against cruzain, a recombinant form of cruzipain. A number of these compounds have been shown to be effective inhibitors of cruzain, having IC50 values in the low nanomolar range. Enzyme activity was monitored via a fluorogenic assay which measured the cleavage of 7-amino-4-methylcoumarin (AMC) from benzyloxycarbonyl-L-phenylalanine-L-arginine-AMC (Z-FR-AMC). The purpose of this study was to carry out advanced kinetic analyses of the thiosemicarbazone compounds that are potent inhibitors in order to elucidate the mechanisms by which they inhibit cruzain and thus gain a better understanding of optimally effective cruzain inhibitors.

Evaluation of inhibitors of cruzain as potential therapeutics for Chagas disease

247th National Meeting (2014)

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