Inhibitors of the major cysteinyl proteinase (GP57/51) impair host cell invasion and arrest the intracellular development of Trypanosoma cruzi in vitro

Meirelles, M. N. L.; Juliano, Luiz; Carmona, Eurı́dice; Silva, Suelen G.; Costa, Emília Chagas; Murta, A. C. M.; Scharfstein, Júlio

doi:10.1016/0166-6851(92)90050-t

Cited by 216 publications

(148 citation statements)

References 34 publications

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“…It has been proposed that cruzipain could have a role in cell invasion (Meirelles et al, 1992) and may be involved in disease pathology (Murta et al, 1990). We therefore investigated, in an in vivo model, whether parasites that overexpressed cruzipain were more infectious and observed how the host reacted to the infection.…”

Section: Epimastigotes That Overexpress Cruzipain Have a Higher Rate mentioning

confidence: 99%

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Overexpression of Cruzipain, the Major Cysteine Proteinase of Trypanosoma cruzi, is Associated with Enhanced Metacyclogenesis

Tomás

Miles

Kelly

1997

European Journal of Biochemistry

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Cruzipain, the major cysteine proteinase of Trypanosoma cruzi has been proposed as a target for chemotherapy against Chagas' disease. To investigate the role of cruzipain we transfected 7: cruzi epimastigotes with a recombinant cosmid containing approximately 20 tandenily repeated cruzipain genes. Transformed cells had multiple episomal copies of the vector and exhibited considerable overexpression of cruzipain activity. The upregulation was maintained throughout the parasite life-cycle, and electrophoretic detection techniques indicated that overexpression was correlated with correctly processed enzyme. Immunoelectron microscopy demonstrated that cruzipain had the same developmentally regulated subcellular localisation in transformed and non-transformed cells. In the insect epimastigote form, the enzyme was restricted to vesicles of the endosomal/lysosomal system, whereas in the intracellular forms it was also readily detectable on the cell surface. Phenotypic analysis of the transformed parasites showed that they had an enhanced ability to undergo metacyclogenesis and suggested an association between overexpression of cruzipain and increased resistance to the cysteiiie proteinase inhibitor Cbz-Phe-Phe-CHN, (where Cbz is benzoyloxycarbonyl). The increased resistance, however, was less than might be expected if cruzipain was the primary target of the inhibitor. Transgenic parasites did not exhibit increased infectivity.

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Section: Epimastigotes That Overexpress Cruzipain Have a Higher Rate mentioning

confidence: 99%

“…Meirelles et al (1992) have shown that treatment with peptidyl diazomethane derivatives leads to arrest of metacyclogenesis and to decreased cellular infection. Peptidyl fluoromethylketone inhibitors have been observed to inhibit intracellular replication and intercellular transmission .…”

mentioning

confidence: 99%

Overexpression of Cruzipain, the Major Cysteine Proteinase of Trypanosoma cruzi, is Associated with Enhanced Metacyclogenesis

Tomás

Miles

Kelly

1997

European Journal of Biochemistry

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“…The parasite infective forms considered herein are metacyclic (MT) and tissue-culture derived trypomastigotes (TCTs), as well as extracellular amastigotes (Fig. 2) 19�4, 19�5), de Lederkremer et al (1980), Lima and Kierszenbaum (1982), Zingales et al (1982), de Lederkremer and Colli (1995); d: Brener (19�9), Silva and Nussenzweig (195�), Howells and Chiari (19�5), Brener (19��), Melo and Brener (19�8), Bice and Zeledon (19�0); e: Miles (19�4),Brener (19��), �lcantara and Brener (19�8), Melo and Brener (19�8), Souto et al (199�) Ouaissi et al (1991), Travassos and �lmeida (199�), Previato et al (1994), Souto-Padrón et al (1994), Parodi et al (1995), Kahn et al (199�), Silva et al (1998, 200�); g: Nogueira and Cohn (19��), Henriquez et al (1981), Lima and Kierszenbaum (1982), Piras et al (1982Piras et al ( , 198�, 1985, Nogueira (198�), Villalta and Kierszenbaum (198�, 1984), Ouaissi et al (1985), Snary (1985), Schenkman et al (1991a), Schenkman and Mortara (1992); h: Piras et al (1985), de Titto and �raujo (198�), Mbawa et al (1991), McKerrow (1991, Schenkman et al (1991b, Eakin et al (1992), Meirelles et al (1992), Chaves et al (199�),Colli (199�), Cross and Takle (199�), Burleigh et al (199�), S...…”

Section: Discussionmentioning

confidence: 99%

A century of research: what have we learned about the interaction of Trypanosoma cruzi with host cells?

Alves

Mortara

2009

Mem. Inst. Oswaldo Cruz

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“…The enzyme is expressed in all developmental forms of different T. cruzi isolates (87)(88). The involvement of cruzipain in host cell invasion and intracellular development was suggested by using peptidyl diazomethane derivatives, a class of irreversible inhibitors of cysteine proteinase (89). A beneficial role by inhibiting cruzipain in mice infected with T. cruzi was observed by treating infected mice with peptide-fluoromethyl ketones (90).…”

Section: Cruzipainmentioning

confidence: 99%

Molecular analysis of early host cell infection by Trypanosoma cruzi

Villalta¹

2008

Front Biosci

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Trypanosoma cruzi, the causative agent of Chagas heart disease, infects heart and other cells leading to cardiac arrest frequently followed by death (1). The disease affects millions of individuals in the Americas and is posing health problems because of blood transmission in the US due to large Latin American immigration (2-3). Since the current drugs present serious side effects and do not cure the chronic infection (4), it is critically important to understand the early process of cellular infection at the molecular and structural levels to design novel inhibitors to block T. cruzi infection. In this review, the authors critically analyze the molecular and cellular basis of early T. cruzi infection and discuss the future directions in this area. The candidate T. cruzi invasive genes and host genes involved in the process of early infection are just beginning to be understood. The trypanosome invasive proteins are excellent targets for intervention. The progress made in the cell biology of T. cruzi infection will also facilitate the development of novel cell-based therapies to ameliorate the disease.

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Inhibitors of the major cysteinyl proteinase (GP57/51) impair host cell invasion and arrest the intracellular development of Trypanosoma cruzi in vitro

Cited by 216 publications

References 34 publications

Overexpression of Cruzipain, the Major Cysteine Proteinase of Trypanosoma cruzi, is Associated with Enhanced Metacyclogenesis

Overexpression of Cruzipain, the Major Cysteine Proteinase of Trypanosoma cruzi, is Associated with Enhanced Metacyclogenesis

A century of research: what have we learned about the interaction of Trypanosoma cruzi with host cells?

Molecular analysis of early host cell infection by Trypanosoma cruzi

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