Disease relevance of Tc00.1047053508173.110

• The major cysteine protease of Trypanosoma cruzi, cruzain, has been previously expressed in Escherichia coli as a fusion polypeptide [1].
• A novel chemotherapy in development for Chagas' disease targets cruzain, the major cysteine protease of Trypanosoma cruzi [2].
• Trypanosoma cruzi, the causative agent of Chagas' heart disease, is a relevant model to explore this possibility because these intracellular parasites rely on their major lysosomal cysteine protease (cruzipain) to invade and multiply in mammalian host cells [3].
• Evidence has now accumulated that cysteine protease inhibitors can selectively arrest replication of a microbial pathogen without untoward toxicity to the host [4].
• As a first step toward applying this strategy to design inhibitors as antiparasitic agents for leishmaniasis, we have isolated and sequenced the full-length clones of two cysteine protease genes from Leishmania major [5].

High impact information on Tc00.1047053508173.110

• Upregulation of the secretory pathway in cysteine protease inhibitor-resistant Trypanosoma cruzi [2].
• Cruzain, the major cysteine protease of the protozoan parasite Trypanosoma cruzi, is a target of rational drug design for chemotherapy of Chagas' disease [6].
• Cysteine protease inhibitors alter Golgi complex ultrastructure and function in Trypanosoma cruzi [6].
• The precise biological role of cruzain in the parasite life cycle and the mechanism involved in the trypanocidal effect of cysteine protease inhibitors are still unclear [6].
• Cruzain, a glycoprotein that transits the Golgi-endosomal pathway, localized to pre-lysosomes/lysosomes in the posterior end of untreated epimastigotes by fluorescent microscopy utilizing either a biotinylated cysteine protease inhibitor to tag the active site, or a specific anti-cruzain antibody [6].

Chemical compound and disease context of Tc00.1047053508173.110

• Targeted libraries of ketone-based cysteine protease inhibitors were synthesized and screened against cruzain, a cysteine protease implicated in Chagas' disease [7].
• Papain-like cysteine proteases are important for the survival of the flagellated protozoa Trypanosoma cruzi, the causative agent of Chagas' Disease. The lysosomal cysteine protease designated as cruzipain or cruzain, is the archetype of a multigene family of related isoforms [8].

Biological context of Tc00.1047053508173.110

• The cysteine protease of Trypanosoma cruzi as a model for antiparasite drug design [9].
• Characterization of the substrate specificity of the major cysteine protease (cruzipain) from Trypanosoma cruzi using a portion-mixing combinatorial library and fluorogenic peptides [10].
• Synthesis and structure-activity relationship study of potent trypanocidal thio semicarbazone inhibitors of the trypanosomal cysteine protease cruzain [11].
• Unlike mammalian lysosomal cysteine proteases, the trypanosomal cysteine protease cruzipain contains a 130-amino acid residue C-terminal domain, in addition to the catalytic domain, and it is stable at neutral pH [12].
• To evaluate the vector and to determine the fidelity of replication we first constructed cosmid libraries and isolated clones containing the T. cruzi major cysteine protease genes (a tandemly repeated array) and the L. donovani trypanothione reductase gene (a single copy gene) [13].

Anatomical context of Tc00.1047053508173.110

• Our results suggest that cysteine protease inhibitors prevent the normal autocatalytic processing and trafficking of cruzain within the Golgi apparatus [6].
• Consistent with a role for cruzipain, the cysteine protease inhibitor N-methylpiperazine-urea-Phe-homophenylalanine-vinylsulfone-benzene impaired the invasion of human smooth muscle cells by strains Dm28c and X10/6 but not by the G isolate [14].
• Falstatin, a Cysteine Protease Inhibitor of Plasmodium falciparum, Facilitates Erythrocyte Invasion [15].

Associations of Tc00.1047053508173.110 with chemical compounds

• Pre-treatment of epimastigotes with cysteine protease inhibitors followed by exposure to brefeldin A induced a more rapid appearance of the cysteine protease inhibitor-induced Golgi alterations [6].
• Cruzipain-rich supernatants of Dm28c trypomastigotes enhanced the infectivity of isolate G parasites twofold, an effect which was abolished by the cysteine protease inhibitor l-trans-epoxysuccinyl-leucylamido-(4-guanidino)butane and by thapsigargin, a drug that induces depletion of the intracellular Ca(2+) stores [14].
• The crystal structures of two hydroxymethyl ketone inhibitors complexed to the cysteine protease cruzain have been determined at 1.1 and 1.2 A resolution, respectively [16].
• Potent second generation vinyl sulfonamide inhibitors of the trypanosomal cysteine protease cruzain [17].

References