Harth, G., Andrews, N., Mills, A. A., Engel, J. C., Smith, R., McKerrow, J. H. (1993) Peptide-fluoromethyl ketones arrest intracellular replication and intercellular transmission of Trypanosoma cruzi. Molecular and Biochemical Parasitology, 58 (1). pp. 17-24. ISSN 01666851 (ISSN)
Abstract
The major proteolytic activity of Trypanosoma cruzi is a cathepsin L-like cysteine protease expressed in all stages of the parasite. As an initial step in identifying possible functions of this enzyme in the life cycle of T. cruzi, and examining its potential as a target for rational drug design, two fluoromethyl ketone-derivatized cysteine protease inhibitors were studied for their effects on T. cruzi infection of mammalian cells. Both inhibitors are irreversible substrate analogues with high specificity for cysteine proteases and minimal toxicity to mammalian cells. While micromolar concentrations of inhibitors had some effect on replication of all parasite stages, the most dramatic arrest of parasite replication occurred at the transformation of trypomastigote to amastigote, and also from amastigote to trypomastigote. It is therefore proposed that the enzyme functions in intracellular protein degradation in some stages of T. cruzi, but also in remodeling of the parasite during transformation between stages. Concentrations of inhibitors necessary to interrupt the parasite life cycle had no observable toxicity to macrophages, fibroblasts or epithelial cells in culture. Differential susceptibility of T. cruzi versus host cysteine proteases to fluoromethyl ketone protease inhibitors suggests that inhibition of the T. cruzi cysteine protease is a potential lead for new chemotherapy of Chagas' disease.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | cysteine fluoromethyl ketone inhibitor protease Trypanosoma cruzi antiprotozoal agent enzyme inhibitor ketone derivative proteinase unclassified drug article chagas disease controlled study enzyme inhibition host parasite interaction nonhuman parasite transmission priority journal protein degradation Amino Acid Chloromethyl Ketones Animal Cathepsin B Cathepsins Dipeptides Dose-Response Relationship, Drug Ketones Morphogenesis Recombinant Proteins Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Vero Cells Mammalia Trypanosoma |
| Subjects: | diseases & disorders diseases & disorders > parasitic diseases organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell regulation organs, tissues, organelles, cell types and functions > cell types and functions |
| CSHL Authors: | |
| Communities: | CSHL labs > Mills lab |
| Depositing User: | Matt Covey |
| Date: | 1993 |
| Date Deposited: | 11 Mar 2013 20:29 |
| Last Modified: | 11 Mar 2013 20:29 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/27762 |
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