Hsp90 is essential in the filarial nematode Brugia pahangi

Devaney, Eileen; O’Neill, Kerry; Harnett, William; Whitesell, Luke; Kinnaird, Jane

doi:10.1016/j.ijpara.2005.01.007

Cited by 49 publications

(54 citation statements)

References 41 publications

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“…Such a regulatory role of Hsp90 has been demonstrated in lower eukaryotes like yeast as well as in higher organisms like mammals. It is not surprising that Hsp90 function has been shown to be essential in yeast, flies, worm, and plants (17,(27)(28)(29)(30) as well as in the malaria parasite (7).…”

Section: Discussionmentioning

confidence: 99%

“…1C binding site, inhibiting Hsp90 function by blocking substrate maturation and subsequently leading to its degradation. Furthermore, despite overall similarity in the GA binding domains of Hsp90s from different organisms, there is a discrepancy in the binding ability of GA. A recent study in free living nematode showed that its Hsp90 is unable to bind GA, whereas Hsp90 of the obligate nematode parasite binds to GA (16,17). The binding affinity of GA to Hsp90 from human host is well established, but its interaction with the malaria parasite Hsp90 has not been elucidated.…”

Section: Pfhsp90 Is a Hyperactive Atpase-allmentioning

confidence: 99%

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Heat Shock Protein 90 as a Drug Target against Protozoan Infections

Pallavi

Roy

Nageshan

et al. 2010

Journal of Biological Chemistry

145

134

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Using a pharmacological inhibitor of Hsp90 in cultured malarial parasite, we have previously implicated Plasmodium falciparum Hsp90 (PfHsp90) as a drug target against malaria. In this study, we have biochemically characterized PfHsp90 in terms of its ATPase activity and interaction with its inhibitor geldanamycin (GA) and evaluated its potential as a drug target in a preclinical mouse model of malaria. In addition, we have explored the potential of Hsp90 inhibitors as drugs for the treatment of Trypanosoma infection in animals. Our studies with full-length PfHsp90 showed it to have the highest ATPase activity of all known Hsp90s; its ATPase activity was 6 times higher than that of human Hsp90. Also, GA brought about more robust inhibition of PfHsp90 ATPase activity as compared with human Hsp90. Mass spectrometric analysis of PfHsp90 expressed in P. falciparum identified a site of acetylation that overlapped with Aha1 and p23 binding domain, suggesting its role in modulating Hsp90 multichaperone complex assembly. Indeed, treatment of P. falciparum cultures with a histone deacetylase inhibitor resulted in a partial dissociation of PfHsp90 complex. Furthermore, we found a well known, semisynthetic Hsp90 inhibitor, namely 17-(allylamino)-17-demethoxygeldanamycin, to be effective in attenuating parasite growth and prolonging survival in a mouse model of malaria. We also characterized GA binding to Hsp90 from another protozoan parasite, namely Trypanosoma evansi. We found 17-(allylamino)-17-demethoxygeldanamycin to potently inhibit T. evansi growth in a mouse model of trypanosomiasis. In all, our biochemical characterization, drug interaction, and animal studies supported Hsp90 as a drug target and its inhibitor as a potential drug against protozoan diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Pfhsp90 Is a Hyperactive Atpase-allmentioning

confidence: 99%

Heat Shock Protein 90 as a Drug Target against Protozoan Infections

Pallavi

Roy

Nageshan

et al. 2010

Journal of Biological Chemistry

145

134

View full text Add to dashboard Cite

show abstract

“…elegans, while demonstrating that Hsp90 from the filarial nematode Brugia pahangi bound to GA beads [35]. Furthermore, in a fluorescence polarization assay, which also utilized worm lysate, we could detect no significant binding of labeled GA to C. elegans extract, while Hsp90 from Brugia extract bound with similar affinity to that of a breast cancer cell line.…”

Section: Hsp90 Differs In Free-living and Parasitic Nematodesmentioning

confidence: 81%

“…In early studies on filarial worms, we demonstrated that inhibition of Hsp90 by GA was sufficient to kill adult B. pahangi [35]. The effect of these compounds on the worms is first manifest by a reduction in Mf output, followed by the irreversible cessation of Mf production.…”

Section: The Pros and Cons Of Hsp90 Inhibitors For The Control Of Parmentioning

confidence: 97%

“…In common with other eukaryotes, filarial worms express relatively high levels of Hsp90, but in contrast to other heat shock proteins, Hsp90 is not significantly upregulated, at either the mRNA or protein level, upon temperature shift from 28 o C to 37 o C (mimicking the vector to mammalian transition) or upon heat shock [34,35]. What then might be the function of Hsp90 in these organisms?…”

Section: Hsp90 Differs In Free-living and Parasitic Nematodesmentioning

confidence: 99%

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Hsp90 Inhibitors in Parasitic Nematodes: Prospects and Challenges

Devaney

Gillan²

2016

CTMC

Self Cite

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Hsp90 inhibitors are well characterized in relation to their effects in a variety of tumors, with several inhibitors in various phases of clinical development. In recent years, the same inhibitor classes have been tested for efficacy in other systems, such as Alzheimer's disease and a variety of infectious disease models, including fungal and parasitic targets. In this article we discuss the repurposing of Hsp90 inhibitors for parasitic disease with a focus on parasitic nematode infections. We summarize the data that indicates that Hsp90 is functionally diverse in different nematode species and we discuss the challenges and prospects for developing these inhibitors as next generation chemotherapeutic tools.

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The HSP90 inhibitor 17‐AAG induced calcium‐mediated apoptosis in filarial parasites

Ahmad

Sharma

Yadav

et al. 2022

Drug Development Research

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The available antifilarial medications are effective only against the larval stage of the filarial parasite. As a result, there is a pressing need for an adulticidal drug.The development of drugs requires the identification of molecular targets that are critical for parasite life. In this study, we observed the effect of 17-N-allyl-17demethoxygeldanamycin on the survival of adult filarial parasites. The 17-N-allyl-17demethoxygeldanamycin (17-AAG) is a derivative of geldanamycin (GA), which is an inhibitor of heat shock protein (HSP)90. It is less toxic as compared to geldanamycin. The motility and viability of the adult filarial parasite Setaria cervi were decreased on exposure to 17-AAG at 2.5 and 5.0 μM/ml concentrations. The 17-AAG treated parasites showed induction of oxidative stress as evidenced by decreased activity of various antioxidant enzymes like glutathione s-transferase, glutathione reductase, thioredoxin reductase, and an increase in ROS production in comparison to control. Oxidative stress may lead to altered calcium homeostasis. Indeed, in 17-AAG treated worms, there was a rise in calcium in the cytosol and mitochondria, as well as a decrease in the ER. We also observed enhanced activity of phospholipase C in the treated parasite, suggesting the opening of calcium channels located on the ER membrane. ER stress is marked by a reduced level of protein disulfide isomerase. Further, 17-AAG treated worms showed an increase in apoptotic marker enzyme activities like calpain, cyt-c, and caspase-3. The 2Dgel electrophoresis technique showed 142 protein spots in the control and 112 spots in the 17-AAG treated parasite. Thus, 17-AAG induced oxidative stress, and altered calcium, and proteostasis of parasites, which led to apoptosis.

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Hsp90 is essential in the filarial nematode Brugia pahangi

Cited by 49 publications

References 41 publications

Heat Shock Protein 90 as a Drug Target against Protozoan Infections

Heat Shock Protein 90 as a Drug Target against Protozoan Infections

Hsp90 Inhibitors in Parasitic Nematodes: Prospects and Challenges

The HSP90 inhibitor 17‐AAG induced calcium‐mediated apoptosis in filarial parasites

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