In vitro effects of gliotoxin, a natural proteasome inhibitor, on the infectivity and proteolytic activity of Toxoplasma gondii

Paugam, A.; Creuzet, C.; Dupouy‐Camet, Jean; Roisin, Marie‐Paule

doi:10.1007/s00436-002-0644-1

Cited by 30 publications

(11 citation statements)

References 14 publications

(20 reference statements)

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“…However, they neither blocked parasite entry nor inhibited PV establishment [71] . Similar results were obtained using another specific inhibitor (gliotoxin), with marked reduction in replication, but parasite penetration of host was not affected [72] .…”

Section: Cysteine Proteinase Inhibitors (Cpis)supporting

confidence: 78%

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (1)

Abaza

2019

Parasitologists United Journal

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Cysteine proteinases (CPs) Being essential for parasite survival, CPs are investigated for development of vaccine candidates and/or novel drugs in protozoal diseases with high mortality and morbidity rates such as malignant malaria, African sleeping sickness and Chagas' disease, as well as neglected tropical diseases such as visceral leishmaniasis, toxoplasmosis, extraintestinal amoebiasis and cryptosporidiosis. Caffrey and Steverding [1] , in their review, introduced a unified nomenclature for kinetoplastid cathepsins (CATHs) and discussed their expressions in different developmental stages, essential functions, as well as genomic organization. They also discussed the feasibility of application of these CPs in development of vaccine candidates. Recent evolution in molecular technology and bioinformatics enable researchers to localize and analyze the biologic cellular functions of several expressed CPs. In addition, CPs abundance in parasites compared to their mammalian hosts attract scientists to search for specific CP inhibitors for development of safe chemotherapeutic agents without host adverse side effects. In this regard, Caffrey et al., [2] reviewed CPs of clan CA, family C1 in kinetoplastids and discussed their biochemical and genetic diversity as well as their genomics in relation to stage-specificity and expression control. The reviewers aimed at utilizing literature date as first step to achieve development of novel drugs and/or vaccine candidates to control visceral leishmaniasis, African sleeping sickness and Chagas' disease. On the other hand, complete genome sequences of three human pathogenic trypanosomatids, T. brucei, T. cruzi and Leishmania spp. followed by in silico analyses allowed the researchers to identify and assign 23, 40 and 33 genes involved in calpains (CALPs) expression in different stages of T. brucei, T. cruzi and L. braziliensis, respectively. In a review article published two years later, the reviewers discussed the biochemical and biological aspects of CALPs expressed in these trypanosomatids. They focused on the fact that knowing the genome sequences in drug-resistant and-sensitive strains will allow the investigators to investigate the inhibitory efficiency of several CALP inhibitors [3]. Furthermore, CPs were utilized as diagnostic markers. In 2005, Brazilian investigators described SDS-PAGE for in situ detection of CP activity using its specific CP inhibitor to differentiate between flagellates isolated from insects and plants [4]. In the same year, a group of scientists from UK employed genomic analysis to identify genes encoding CALPs in three human kinetoplastids; L. major, T. cruzi, and T. brucei.

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Section: Cysteine Proteinase Inhibitors (Cpis)supporting

confidence: 78%

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (1)

Abaza

2019

Parasitologists United Journal

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“… [34] – [40] , Leishmania spp. [41] – [45] , Toxoplasma gondii [46] , Trypanosoma cruzi [47] , [48] and T. brucei [49] , [50] the proteasome has been long investigated as a potential drug target. In addition, the anti-malarial activity of BTZ and one of its derivatives was assessed earlier [51] .…”

Section: Discussionmentioning

confidence: 99%

Profound Activity of the Anti-cancer Drug Bortezomib against Echinococcus multilocularis Metacestodes Identifies the Proteasome as a Novel Drug Target for Cestodes

et al. 2014

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A library of 426 FDA-approved drugs was screened for in vitro activity against E. multilocularis metacestodes employing the phosphoglucose isomerase (PGI) assay. Initial screening at 20 µM revealed that 7 drugs induced considerable metacestode damage, and further dose-response studies revealed that bortezomib (BTZ), a proteasome inhibitor developed for the chemotherapy of myeloma, displayed high anti-metacestodal activity with an EC50 of 0.6 µM. BTZ treatment of E. multilocularis metacestodes led to an accumulation of ubiquinated proteins and unequivocally parasite death. In-gel zymography assays using E. multilocularis extracts demonstrated BTZ-mediated inhibition of protease activity in a band of approximately 23 kDa, the same size at which the proteasome subunit beta 5 of E. multilocularis could be detected by Western blot. Balb/c mice experimentally infected with E. multilocularis metacestodes were used to assess BTZ treatment, starting at 6 weeks post-infection by intraperitoneal injection of BTZ. This treatment led to reduced parasite weight, but to a degree that was not statistically significant, and it induced adverse effects such as diarrhea and neurological symptoms. In conclusion, the proteasome was identified as a drug target in E. multilocularis metacestodes that can be efficiently inhibited by BTZ in vitro. However, translation of these findings into in vivo efficacy requires further adjustments of treatment regimens using BTZ, or possibly other proteasome inhibitors.

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“…Interestingly, gliotoxin has previously been implicated in inhibition of proteolytic activity of human and toxoplasma proteasomes. 53,54 The cobalamin-independent methionine synthase MetH/D showed a similar response to DTG treatment, -dependent metalloenzymes, causing extreme growth inhibition. Additionally, Zn(DTG) cannot be converted to BmGT via GtmA.…”

Section: +mentioning

confidence: 99%

Systems impact of zinc chelation by the epipolythiodioxopiperazine dithiol gliotoxin inAspergillus fumigatus: a new direction in natural product functionality

et al. 2018

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Significance to metallomicsDithiol gliotoxin is a near-terminal biosynthetic intermediate from the gliotoxin biosynthetic pathway in the human pathogen Aspergillus fumigatus. Chemically reduced gliotoxin, dithiol gliotoxin (DTG), is revealed as a biological zinc chelator, and conversely, zinc can relieve the hitherto cryptic fungal autotoxicity of DTG. There is a systems-wide impact of zinc chelation by DTG on the fungal proteome, and we suggest it is DTG, as opposed to gliotoxin, which chelates zinc from metalloproteins. Since gliotoxin can be sequestered by both fungi and bacteria, our findings infer a new avenue to interfere with, and exploit, cellular zinc homeostasis in microorganisms. IntroductionGliotoxin and holomycin are microbial natural products, which are produced by fungal and bacterial spp., respectively (Fig. 1). [1][2][3] Both are low molecular mass metabolites, and each contains a disulphide bridge formed by the action of oxidoreductases, namely GliT and HlmI, on the respective dithiol precursor (Fig. 1). [4][5][6] Disulphide bridge formation is essential for microbial self-protection against these reactive dithiol intermediates, and is a pre-requisite for the Major Facilitator Superfamily transporter GliA-mediated secretion of gliotoxin by Aspergillus fumigatus. 5-8Both metabolites are also present as bis-thiomethylated forms, and gliotoxin bis-thiomethyltransferase GtmA converts dithiol gliotoxin (DTG) to bis-dethiobis(methylthio)gliotoxin (BmGT) in A. fumigatus, whereas the origin of the cognate activity against dithiol holomycin in Streptomyces clavuligeris is unknown (Fig. 1). 9,10Bernardo et al. have shown that upon uptake by eukaryotic cells,

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In vitro effects of gliotoxin, a natural proteasome inhibitor, on the infectivity and proteolytic activity of Toxoplasma gondii

Cited by 30 publications

References 14 publications

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (1)

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (1)

Profound Activity of the Anti-cancer Drug Bortezomib against Echinococcus multilocularis Metacestodes Identifies the Proteasome as a Novel Drug Target for Cestodes

Systems impact of zinc chelation by the epipolythiodioxopiperazine dithiol gliotoxin inAspergillus fumigatus: a new direction in natural product functionality

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