Inhibition of a Plasmodium vinckei cysteine proteinase cures murine malaria.

Rosenthal, Philip J.; Lee, G K; Smith, Robin

doi:10.1172/jci116262

Cited by 155 publications

(94 citation statements)

References 11 publications

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“…Our results are consistent with prior observations that the trophozoite stage is most sensitive to treatment with cysteine protease inhibitors (29) and with the conclusion that the principal activity of these agents is to block hemoglobin hydrolysis. Falcipain-2 and falcipain-3 seem to be the principal hemoglobinases that are acted on by cysteine protease inhibitors, as supported by correlations in many classes of inhibitors between action against these enzymes, inhibition of hemoglobin hydrolysis, and prevention of parasite development (16,17,30,31). It remains unclear whether effects of cysteine protease inhibitors on erythrocyte rupture were due only to the consequences of the inhibition of hemoglobin hydrolysis, or whether inhibition of other activities of cysteine proteases also played a role.…”

Section: Discussionmentioning

confidence: 96%

Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites

Sijwali

Kato

Seydel

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

121

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Among potential new targets for antimalarial chemotherapy are Plasmodium falciparum cysteine proteases, known as falcipains. Falcipain-2 and falcipain-3 are food vacuole hemoglobinases that may have additional functions. The function of falcipain-1 remains uncertain. To better characterize the role of falcipain-1 in erythrocytic parasites, we disrupted the falcipain-1 gene and characterized recombinant parasites. Disruption of the falcipain-1 gene was confirmed with Southern blots, and loss of expression of falcipain-1 was confirmed with immunoblots and by loss of labeling with a specific protease inhibitor. Compared with wild-type parasites, falcipain-1 knockout parasites developed normally, with the same morphology, multiplication rate, and invasion efficiency, and without significant differences in sensitivity to cysteine protease inhibitors. In wild-type and knockout parasites, cysteine protease inhibitors blocked hemoglobin hydrolysis in trophozoites, with a subsequent block in rupture of erythrocytes by mature schizonts, but they did not inhibit erythrocyte invasion by merozoites. Our results indicate that although falcipain-1 is expressed by erythrocytic parasites, it is not essential for normal development during this stage or for erythrocyte invasion.

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Section: Discussionmentioning

confidence: 96%

Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites

Sijwali

Kato

Seydel

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

121

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“…In malaria parasites, where a remarkably similar network of both cysteine and aspartic proteases functions to degrade hemoglobin, treatment of parasite cultures with a combination of cysteine and aspartic protease inhibitors is synergistic (55). Nevertheless, inhibitors of cysteine proteases alone cured malaria in a mouse model (56).…”

Section: Discussionmentioning

confidence: 99%

A Multienzyme Network Functions in Intestinal Protein Digestion by a Platyhelminth Parasite

Delcroix

Sajid

Caffrey

et al. 2006

Journal of Biological Chemistry

214

205

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Proteases frequently function not only as individual enzymes but also in cascades or networks. A notable evolutionary switch occurred in one such protease network that is involved in protein digestion in the intestine. In vertebrates, this is largely the work of trypsin family serine proteases, whereas in invertebrates, cysteine proteases of the papain family and aspartic proteases assume the role. Utilizing a combination of protease class-specific inhibitors and RNA interference, we deconvoluted such a network of major endopeptidases functioning in invertebrate intestinal protein digestion, using the parasitic helminth, Schistosoma mansoni as an experimental model. We show that initial degradation of host blood proteins is ordered, occasionally redundant, and substrate-specific. Although inhibition of parasite cathepsin D had a greater effect on primary cleavage of hemoglobin, inhibition of cathepsin B predominated in albumin degradation. Nevertheless, in both cases, inhibitor combinations were synergistic. An asparaginyl endopeptidase (legumain) also synergized with cathepsin B and L in protein digestion, either by zymogen activation or facilitating substrate cleavage. This protease network operates optimally in acidic pH compartments either in the gut lumen or in vacuoles of the intestinal lining cells. Defining the role of each of these major enzymes now provides a clearer understanding of the function of a complex protease network that is conserved throughout invertebrate evolution. It also provides insights into which of these proteases are logical targets for development of chemotherapy for schistosomiasis, a major global health problem.

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“…Specific CP inhibitors not only can kill L. major in vitro, but also can cure L. major infection in BALB/c mice (53). In fact, inhibitors of CPs from T. cruzi (54), T. brucei (55), and Plasmodium (56,57) have demonstrated efficacy in preliminary animal studies, and K11777, a CP inhibitor of the T. cruzi enzyme cruzipain, will enter clinical trials for Chagas disease very soon (32). It is also interesting that CP inhibitors such as N-benzoyloxycarbonyl-phe-aladiazomethylketone, which do not directly kill L. mexicana axenic (cultured) amastigotes in liquid culture, do induce the killing of parasites in infected macrophages, supporting a role for CPs in suppression of host defense (6).…”

Section: Discussionmentioning

confidence: 99%

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

Buxbaum

Denise

Coombs

et al. 2003

The Journal of Immunology

108

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C3H mice infected with Leishmania mexicana fail to develop a protective Th1 response, and are unable to cure. In this study, we show that L. mexicana cysteine proteases suppress the antileishmanial immune response. Previous studies demonstrated that deletion of the entire multicopy cysteine protease B (CPB) gene array in L. mexicana is associated with decreased parasite virulence, potentially attributable to factors related to parasite fitness rather than to direct effects on the host immune response. We now show that C3H mice infected with the L. mexicana deletion mutant (Δcpb) initially develop lesions that grow at rates comparable to those of wild-type L. mexicana-infected mice. However, in contrast to controls, Δcpb-induced lesions heal with an accompanying Th1 immune response. Lesion resolution was Th1 dependent, as Δcpb-infected IL-12p40−/− and STAT4−/− mice developed high parasite burdens and progressive disease. Moreover, when L. major was transfected with a cosmid expressing multiple L. mexicana CPB genes, this parasite induced a significantly lower IFN-γ response compared with wild-type L. major. These data indicate that cysteine proteases of L. mexicana are critical in suppressing protective immune responses and that inhibition of CPB may prove to be a valuable immunomodulatory strategy for chronic forms of leishmaniasis.

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Inhibition of a Plasmodium vinckei cysteine proteinase cures murine malaria.

Cited by 155 publications

References 11 publications

Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites

Plasmodium falciparum cysteine protease falcipain-1 is not essential in erythrocytic stage malaria parasites

A Multienzyme Network Functions in Intestinal Protein Digestion by a Platyhelminth Parasite

Cysteine Protease B of Leishmania mexicana Inhibits Host Th1 Responses and Protective Immunity

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