Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity

Posfai, Dora; Eubanks, Amber L.; Keim, Allison I.; Lu, Kuan-Yi; Wang, Grace Z.; Hughes, Philip F.; Kato, Nobutaka; Haystead, Timothy; Derbyshire, Emily R.

doi:10.1128/aac.01799-17

Cited by 36 publications

(38 citation statements)

References 67 publications

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“…Activation of sporozoite intracellular calcium signaling cascades in response to the mammalian microenvironment was evident with increased abundance of calmodulin, CDPK7, protein kinase 4 (PK4), and Receptor of Activated Protein C Kinase 1 (RACK1). Our results also support recent reports that heat shock proteins (HSP) are critical for liver-stage parasite development as HSP70, HSP70-2, HSP90, and PVP01_1405400 were amongst the highest differentially expressed genes 51 . In order to rapidly transition between pivotal life-cycle stages, Plasmodium uses translational repression to regulate pre-transcribed mRNA stockpiles that encode required proteins.…”

Section: Resultssupporting

confidence: 91%

Unraveling the Plasmodium vivax sporozoite transcriptional journey from mosquito vector to human host

Roth

Adapa

Zhang

et al. 2018

Sci Rep

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Malaria parasites transmitted by mosquito bite are remarkably efficient in establishing human infections. The infection process requires roughly 30 minutes and is highly complex as quiescent sporozoites injected with mosquito saliva must be rapidly activated in the skin, migrate through the body, and infect the liver. This process is poorly understood for Plasmodium vivax due to low infectivity in the in vitro models. To study this skin-to-liver-stage of malaria, we used quantitative bioassays coupled with transcriptomics to evaluate parasite changes linked with mammalian microenvironmental factors. Our in vitro phenotyping and RNA-seq analyses revealed key microenvironmental relationships with distinct biological functions. Most notable, preservation of sporozoite quiescence by exposure to insect-like factors coupled with strategic activation limits untimely activation of invasion-associated genes to dramatically increase hepatocyte invasion rates. We also report the first transcriptomic analysis of the P. vivax sporozoite interaction in salivary glands identifying 118 infection-related differentially-regulated Anopheles dirus genes. These results provide important new insights in malaria parasite biology and identify priority targets for antimalarial therapeutic interventions to block P. vivax infection.

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Section: Resultssupporting

confidence: 91%

Unraveling the Plasmodium vivax sporozoite transcriptional journey from mosquito vector to human host

Roth

Adapa

Zhang

et al. 2018

Sci Rep

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“…Despite the high sequence conservation amongst Hsp90 homologues of P. falciparum relative to their counterparts from humans and other species [17], their small differences may suffice to allow design of inhibitors which specifically target only the parasite’s Hsp90s [110]. It has been demonstrated that PfHsp90 (PF3D7_0708400) can be inhibited by a number of known Hsp90 inhibitors, and that growth of both the blood stages and liver stages is reduced by this treatment [56,59,110]. Among the tested inhibitors are GA, 17-DMAG, ganetespib, harmine, and PU-H71 [59,110].…”

Section: Implications For Therapeutic Interventionmentioning

confidence: 99%

Partners in Mischief: Functional Networks of Heat Shock Proteins of Plasmodium falciparum and Their Influence on Parasite Virulence

2019

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The survival of the human malaria parasite Plasmodium falciparum under the physiologically distinct environments associated with their development in the cold-blooded invertebrate mosquito vectors and the warm-blooded vertebrate human host requires a genome that caters to adaptability. To this end, a robust stress response system coupled to an efficient protein quality control system are essential features of the parasite. Heat shock proteins constitute the main molecular chaperone system of the cell, accounting for approximately two percent of the malaria genome. Some heat shock proteins of parasites constitute a large part (5%) of the ‘exportome’ (parasite proteins that are exported to the infected host erythrocyte) that modify the host cell, promoting its cyto-adherence. In light of their importance in protein folding and refolding, and thus the survival of the parasite, heat shock proteins of P. falciparum have been a major subject of study. Emerging evidence points to their role not only being cyto-protection of the parasite, as they are also implicated in regulating parasite virulence. In undertaking their roles, heat shock proteins operate in networks that involve not only partners of parasite origin, but also potentially functionally associate with human proteins to facilitate parasite survival and pathogenicity. This review seeks to highlight these interplays and their roles in parasite pathogenicity. We further discuss the prospects of targeting the parasite heat shock protein network towards the developments of alternative antimalarial chemotherapies.

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“…In light of the importance of both PfHsp70-1 and PfHsp90 in the survival of the malaria parasite, there has been growing interest in identifying inhibitors targeting the function of these two molecular chaperones. Compounds that inhibit PfHsp70-1 [14; 15; 16] and PfHsp90 [17,9] have been identified, and some of them exhibit antiplasmodial activity. Some compounds that target PfHsp90 function reverse parasite resistance to traditional antimalarial drugs, such as chloroquine (reviewed in [18]).…”

Section: Introductionmentioning

confidence: 99%

Biophysical analysis ofPlasmodium falciparumHsp70-Hsp90 organizing protein (PfHop) reveals a monomer that is characterised by folded segments connected by flexible linkers

Makumire

Zininga

Vahokoski

et al. 2019

Preprint

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Plasmodium falciparum causes the most lethal form of malaria. The cooperation of heat shock protein (Hsp) 70 and 90 is important for folding of a select number of cellular proteins that are crucial for cyto-protection and development of the parasites. Hsp70 and Hsp90 are brought into a functional complex that allows substrate exchange by stress inducible protein 1 (STI1), also known as Hsp70-Hsp90 organizing protein (Hop). P. falciparum Hop (PfHop) co-localises and occurs in complex with the parasite cytosolic chaperones, PfHsp70-1 and PfHsp90. Here, we characterised 2 the structure of recombinant PfHop using synchrotron radiation circular dichroism (SRCD) and small-angle X-ray scattering. Structurally, PfHop is a monomeric, elongated but folded protein, in agreement with its predicted TPR domain structure. Using SRCD, we established that PfHop is unstable at temperatures higher than 40 °C. This suggests that PfHop is less stable at elevated temperatures compared to its functional partner, PfHsp70-1, that is reportedly stable at temperatures as high as 80 °C. These findings contribute towards our understanding of the role of the Hop-mediated functional partnership between Hsp70 and Hsp90.

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Identification of Hsp90 Inhibitors with Anti-Plasmodium Activity

Cited by 36 publications

References 67 publications

Unraveling the Plasmodium vivax sporozoite transcriptional journey from mosquito vector to human host

Unraveling the Plasmodium vivax sporozoite transcriptional journey from mosquito vector to human host

Partners in Mischief: Functional Networks of Heat Shock Proteins of Plasmodium falciparum and Their Influence on Parasite Virulence

Biophysical analysis ofPlasmodium falciparumHsp70-Hsp90 organizing protein (PfHop) reveals a monomer that is characterised by folded segments connected by flexible linkers

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