Targeting Conserved Pathways as a Strategy for Novel Drug Development: Disabling the Cellular Stress Response

  • Adrienne L. EdkinsEmail author
  • Gregory L. BlatchEmail author


The ability to respond to and cope with stress at a molecular level is essential for cell survival. The stress response is conserved across organisms by the expression of a group of molecular chaperones known as heat shock proteins (HSP). HSP are ubiquitous and highly conserved proteins that regulate cellular protein homeostasis and trafficking under physiological and stressful conditions, including diseases such as cancer and malaria. HSP are good drug targets for the treatment of human diseases, as the significant functional and structural data available suggest that they are essential for cell survival and that, despite conservation across species, there are biophysical and biochemical differences between HSP in normal and disease states that allow HSP to be selectively targeted. In this chapter, we review the international status of this area of research and highlight progress by us and other African researchers towards the characterisation and targeting of HSP from humans and parasites from Plasmodium and Trypanosoma as drug targets.


Heat Shock Protein Cancer Stem Cell Molecular Chaperone HSP90 Inhibitor Heat Shock Transcription Factor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

4.1 Introduction to the Cellular Stress Response

The biological activity of proteins is dependent on the ability to assume and maintain the appropriate three-dimensional biophysical structure. Despite the fact that the primary amino acid sequence is sufficient to define the three-dimensional structure of a protein [1], the crowded cellular environment and molecular stress often result in protein misfolding and aggregation. Stress at the biological level can be defined as any stimulus or condition, such as extreme temperature, oxidative radicals, enhanced growth rate and xenobiotics, that perturbs the correct function of the cell, the result of which is the disruption of protein homeostasis. To cope with these conditions, the organism responds by inducing the expression of a series of highly conserved proteins, known as heat shock proteins (HSP), which function as molecular chaperones to overcome the effects of protein misfolding and aggregation. A molecular chaperone is defined as a protein that is capable of interacting with and stabilising non-native protein structures or nascent polypeptides to prevent aggregation and promote the formation of correct, functional conformations [2]. Since the discovery of HSP in heat-treated Drosophila cells in the early 1960s, a significant amount of research has been devoted to the characterisation of the role these proteins play in physiological and stressful processes with the cell [3, 4, 5]. The response to stress is conserved across organisms; the ability to respond to stress involves molecular chaperones that regulate the integrity of cellular proteins. As protein homeostasis is central to all organisms, cellular stress and molecular chaperone function has been linked to a range of human disorders. HSP have been implicated in a range of pathologies that are linked by the core element of cellular stress [6].

4.2 Heat Shock Proteins as Molecular Chaperones

The ability of HSP to act as molecular chaperones is integral to their protective roles in the cell [7]. Molecular chaperones catalyse the refolding of stress-denatured or nascent polypeptides in addition to regulating the assembly of oligomeric proteins, protein transport and degradation and protein–protein interactions. Molecular chaperones are catalysts in the folding process, in the sense that they do not actively fold proteins, but rather assist folding by preventing non-productive or aggregation reactions and do not constitute part of the final protein structure [8]. HSP may be expressed constitutively or induced by the binding of heat shock transcription factors (HSF) to specific heat shock elements (HSE). Stress induces the phosphorylation of the HSF, leading to the formation of trimeric HSF species that bind the HSE and stimulate expression of the HSP [9]. HSP have been identified in almost all organisms, from bacteria to lower and higher eukaryotes, and show a high level of conservation across species. They are classified and named on the basis of their molecular size, for example, HSP70 will have a molecular weight of approximately 70 kDa. To date, a number of HSP families have been described. These are the HSP100, HSP90, HSP70, HSP60, HSP40 and the small HSP (sHSPs; ~18–43 kDa) families [8, 10]. The link between cell stress, molecular chaperones and human disease has made HSP attractive drug targets. In particular, the focus has been on the development of inhibitors of the HSP90 and HSP70 families of molecular chaperones as drug targets for the treatment of cancer and parasitic diseases.

4.2.1 Heat Shock Protein 90 (HSP90)

In eukaryotic cells, HSP90 species are some of the most abundant molecular chaperones [11]. The human genome encodes five distinct HSP90 genes. Cytosolic HSP90 has two isoforms, the α and β isoforms, which display 85% sequence identity and are encoded for by separate genes that arose from duplication of the original HSP90A gene [12]. HSP90α expression is defined as more inducible than that of HSP90β [13]. HSP90 isoforms are also expressed in the mitochondria (HSP75/TRAP-1), the endoplasmic reticulum (GRP94/GRP96) and under certain conditions, HSP90α, HSP90β and GP96 isoforms have been identified in the plasma membrane or extracellular matrix. The genomes of the parasites Plasmodium falciparum and Trypanosoma cruzi encode 11 and 4 different HSP90 genes, respectively [14]. While both parasites encode cytosolic and ER isoforms of HSP90, they do not encode for the α and β cytosolic isoforms that are found in humans [15]. While eukaryotic HSP90 is essential for cell survival, bacterial HSP90 (HTPG) is dispensable for cell growth. HSP90 is also subject to post-translational modification, including s-nitrosylation, phosphorylation, methylation and acetylation, which may influence its function and cellular localisation [11, 16, 17, 18, 19, 20].

HSP90 functions as a dimer, with each monomer consisting of three highly conserved functional domains, namely an N-terminal domain (25 kDa), a middle (M) domain (35 kDa) and a C-terminal domain (12 kDa) [21, 22]. The N-terminal and M-domain are connected by a charged linker region, which varies in length and amino acid composition according to the species or isoform (and is entirely absent from the prokaryotic HSP90) [23, 24]. The N-terminal domain contains the primary binding site for ATP/ADP [25], as determined by crystallisation studies on both yeast and human HSP90. This ATP/ADP binding site is the same as that bound by the natural HSP90 inhibitor, geldanamycin [26], which can also bind to HSP90 from other species, including P. falciparum [27] and T. cruzi [28]. The C-terminal domain is the site of dimerisation of HSP90 [29] and contains the MEEVD motif which is the primary binding site for the TPR-containing co-chaperones, such as HOP (HSP70/HSP90 organising protein) [30, 31]. The structure of full-length HSP90 has been determined at low resolution by cryo-EM [32], while each of these functional domains has been crystallised independently.

4.2.2 Heat Shock Protein 70 (HSP70)

The HSP70 molecular chaperone family is composed of members that are essential for correct protein folding, transport of proteins to different sub-cellular compartments and degradation of unstable proteins in the cell [33]. HSP70 isoforms are found in most species. We have demonstrated that even the ancient coelacanth [34] encodes a functional HSP70, as do protozoan parasites such as P. falciparum and T. cruzi. There are 13 different isoforms of HSP70 in humans, with 6 isoforms in P. falciparum and 12 in T. brucei [35, 36]. HSP70 have three functional domains, the N-terminal ATPase domain (~44 kDa), substrate binding region (~18 kDa) and a variable C-terminal region (~10 kDa) that is the site of specific interactions with other proteins, such as HOP [31, 37]. The ATPase domain of HSP70 forms two distinct, equally sized structural lobes, separated from each other by a deep cleft, which is the binding site of ATP [38, 39]. ATP hydrolysis by the ATPase domain of HSP70s is central to the role of the protein as a chaperone during assisted protein folding [40]. Despite the basic HSP70 structure being conserved in HSP70 from different organisms [36, 39, 41], there is evidence that there are differences between HSP70 from different organisms that may be exploited to selectively inhibit the HSP70 from certain organisms [42].

4.3 Molecular Chaperones as Drug Targets in Africa

Biological molecules are required to conform to a set of criteria if they are to be considered potential drug targets [43]. Molecular chaperones, and in particular HSP90 and HSP70, are currently considered as bona fide biological targets for drug development as they conform to many of these criteria [43]. Ideally, a drug target should be essential for the development of the disorder, but absent under normal conditions, to allow selective targeting of diseased and non-healthy cells. HSP are important in the development of human disorders including cancer and are conserved across different species of human parasites, probably because they are often vital or essential to survival of the parasite. HSP70 and HSP90 are among the most well-characterised chaperones, with functional and structural data available for different protein isoforms from a range of species. In addition, the naturally occurring inhibitor of HSP90, the ansamycin antibiotic geldanamycin (GA), has facilitated the rational development of HSP90 inhibitors, many of which are analogues of GA (e.g. 17-AAG, 17-DMAG), as well as the search for numerous other natural products that have the potential to be HSP90 inhibitors. The targeting of such highly conserved proteins of human parasites may not resonate with current dogmas of drug discovery, especially in terms of selectivity for the diseased state over the normal condition (such as parasite over human host or cancer cell versus normal cell). However, highly conserved proteins that are essential for cell survival are likely to evolve considerably slower than other less conserved protein families, making them less susceptible to variation under selection pressure, a desirable attribute for any potential drug target. There is also evidence that despite the high levels of conservation, these HSP are not identical and that there are functional and structural differences that may be exploited. In fact, there is even evidence that disease states can generate HSP with different biophysical and biochemical characteristics to their counterparts in normal cells, meaning that the same protein may be biochemically distinct from the normal cell. For example, 17-AAG was found to have a higher affinity for HSP90 in transformed cells compared to normal cells and is currently in clinical trials as an anti-cancer agent [44]. Our research into the identification of inhibitors of HSP90 and HSP70 in protozoan parasites and in cancer is based on our fundamental understanding of these chaperones as a result of comparative studies of the chaperones in humans and parasites. We have identified HSP70 and HSP90 as potential drug targets in the treatment of cancer, malaria and trypanosomiasis and have used the biochemical differences between these proteins to screen potential inhibitors.

4.3.1 Molecular Chaperones of Protozoan Parasites

We and others have begun to scrutinise the chaperone machineries of the causative agents of certain infectious diseases of humans, such as malaria (P. falciparum; reviewed in [36, 45, 46]) and the various trypanosomiases (Trypanosoma brucei and T. cruzi; reviewed in [35]). These parasites have evolved chaperone systems to cope with the extreme demands of cyclical development through physiologically diverse host and vector systems [14]. HSP70 and HSP90, in particular, are expressed at critical developmental stages and persist at high levels in the infectious stages of these parasites. Therefore, it is not surprising that inhibitors of HSP90 (e.g. GA) have been shown to arrest the growth of these parasites [27, 28, 47]. Therefore, plasmodial HSP90 (PfHSP90) is an obvious anti-plasmodial drug target, and promising pre-clinical tests have been conducted using GA and its derivatives [48]. We are discovering that while there is a high degree of conservation at the sequence level between parasitic and human HSPs, there are major structural and functional differences that suggest that the parasitic HSP can be selectively targeted [36, 49].

We and others have conducted extensive biochemical and cell biological studies on the major cytosolic and inducible plasmodial HSP70, PfHSP70-1. As expected, it is a bona fide chaperone, exhibiting ATPase and protein aggregation suppression activities [50, 51, 52], and capable of functionally substituting for both a bacterial [50] and a yeast HSP70 [53]. It is also a highly abundant protein expressed at all erythrocytic stages of the P. falciparum life cycle, with increased expression after heat shock [54, 55]. Importantly, there is strong evidence that PfHSP70-1 is relatively thermostable compared to human HSP70 (hHSP70) and capable of functioning optimally at temperatures around 50°C [56]. In addition, there are biochemical differences between PfHSP70-1 and hHSP70 at the level of ATP affinity and ATPase activity, and structural modelling has identified differences at their HSP40-binding sites [51, 57].

While HSP70 is considered an emerging drug target [58], including PfHSP70-1 [59, 60], there have been limited studies on the development of small molecule modulators of HSP70 with anti-plasmodial activity (Table 4.1). The Brodsky Laboratory has pioneered the development of HSP70 small molecule modulators [64] and recently published promising findings on potential modulators of PfHSP70-1 derived from pyrimidinone-based compounds [65, 67]. We tested some of these compounds in our recent side-by-side study of PfHSP70-1 and hHSP70, confirming that certain pyrimidinones differentially inhibited PfHSP70-1 and hHSP70 (MAL3-39 and DMT002264; [68]). We have started to screen for modulators of PfHSP70-1, using libraries of compounds known to have anti-cancer or anti-plasmodial activity. We discovered that lapachol and certain of its derivatives were able to inhibit the chaperone activity of PfHSP70-1, with lapachol exhibiting specificity towards PfHSP70-1 [42]. We have also screened compounds of marine origin and identified a novel class of inhibitors of PfHSP70-1 (malonganenones) that also showed anti-plasmodial activity [42]. These studies represent a platform for the benchmarking of further hit compounds from recent large-scale screens [72]. All of these PfHSP70-1 inhibitors represent potential hits for the development of leads for anti-plasmodial drug discovery. However, they also represent useful molecular probes for elucidating the mechanism of action of plasmodial chaperones compared to their human homologues.
Table 4.1

HSP70 small molecule modulators with anti-plasmodial activitya


Binding site

Biological activity


15-Deoxyspergualin (DSG)



[52, 61, 62, 63]

Pyrimidinone–peptoid (e.g. MAL3-101)


Anti-cancer and anti-plasmodial

[64, 65, 66]

Pyrimidinone–peptoid (e.g. MAL3-39, DMT3024, DMT2264)



[65, 67, 68]

Dihydropyrimidines (e.g. 116-9e)

HSP40-binding site



Lapachol derivatives


Anti-cancer and anti-plasmodial

[42, 70, 71]





aCompounds with known anti-plasmodial activity, or structurally related compounds yet to be shown to have anti-plasmodial activity

bND = not determined

4.3.2 Human Molecular Chaperones in Cancer

HSP90 is known anecdotally as the ‘cancer chaperone’ due to its ability to exclusively mediate the folding and stability of numerous transcription factors and signalling intermediates in vivo. Many of these so-called client proteins of HSP90 are oncogenes that are either mutated or upregulated in a range of cancers. HSP90 maintains its client proteins in an inactive, but easily inducible, state [73]. As these states are often inherently unstable and labile in the absence of substrate, the role of the HSP90 multi-chaperone complex is to enhance client protein stability [74]. Therefore, using HSP90 as an anti-cancer target allows the simultaneous inhibition of multiple signalling pathways [75]. The molecular chaperone activity of HSP90 is regulated by conformational changes which are dependent on two factors. The first is the intrinsic ATPase activity of HSP90, the importance of which is demonstrated by the fact that mutations that result in either a loss of ATP binding or ATP hydrolysis inhibit both the in vitro and in vivo functions of HSP90. This fact is exploited in drug discovery as many of the naturally occurring or synthetic HSP90 inhibitors bind to the ATP binding site within the N terminus of HSP90. The second factor is the association of HSP90 with a range of co-chaperones (HSP70, HSP40, HOP, p23, immunophilins) into a multi-chaperone complex [11, 76]. HSP90, in association with client protein and co-chaperones, is considered ‘complexed’ or activated, conditions under which HSP90 displays an enhanced sensitivity to and binding of anti-HSP90 drugs compared to free/uncomplexed HSP90 [77, 78].

The inhibition of a number of these pathways through targeting of HSP90 is already being harnessed to develop anti-cancer agents. GA is a specific inhibitor of HSP90 ATPase activity, and its synthetic derivatives (17-AAG, 17-DMAG etc.) are leading the current focus in HSP90 inhibitors as anti-cancer agents [79, 80, 81, 82]. The HSP90-directed drug development process has been greatly facilitated by the fact that many natural products, including GA, novobiocin, gambogic acid, radicicol, epilgallocatechin-3-gallate (EGCG) and taxol, have been found to be HSP90 inhibitors [83]. Many of these compounds show structural similarity in that they possess multiple quinone and/or coumarin ring structures (Fig. 4.1), structural similarity that has facilitated the rational design of analogues of these natural inhibitors. The screening of indigenous natural products from Africa has the potential to identify a number of putative HSP90 inhibitors with anti-cancer or anti-parasite activity and is a major research focus for many groups [84, 85].
Fig. 4.1

Structural similarity between known natural product inhibitors of HSP90. Many of the current HSP90 inhibitors are natural products, which show structural similarity. A number of indigenous compounds isolated from South Africa sources show similarity to these compounds and therefore are potential inhibitors of HSP90 function

In addition to its potential as a general anti-cancer drug target, HSP90 has recently been considered as a treatment for certain cell subtypes within cancers. Extracellular HSP90 protein is expressed on the surface of a range of cell types, including melanoma, fibrosarcoma, breast adenocarcinoma and neuronal cells [86, 87, 88, 89] and linked to cell migration, metastasis and invasion of cancer cells. Selective inhibition of only surface HSP90 reduced migration of a range of cancer cell types [81]; this may offer a unique therapeutic opportunity for the treatment of metastasis, particularly since over 90% of deaths from cancer are as a result of cancer spread (metastasis). Similarly, HSP90 is emerging as a potential drug target for the removal of a specific subpopulation of cancer cells, known as cancer stem cells (CSC). The CSC hypothesis describes cancer development and maintenance as being driven by cancer cells that display stem-like properties (reviewed by us in [90]). Cancer stem cells are cancer cells that, like normal tissue stem cells, are capable of both self-renewal and differentiation, which accounts for tumour heterogeneity. These cells are thought to control tumour development, just as normal tissue stem cells are required for organ development [91, 92, 93]. CSC populations are relevant to cancer drug discovery due to their potential role in metastasis and cancer recurrence, the latter as a result of CSC’s apparent resistance to chemotherapy and radiotherapy [94, 95]. We have linked HSP90 function to stem-cell-associated pathways that may be important in CSC function [96]. We and others have shown that STAT3 is an HSP90 client protein and the LIF/STAT3 pathway is important in self-renewal of embryonic stem cells [97, 98]. The HSP90 inhibitor 17-AAG was effective at inhibiting growth of both glioma cells and glioma cancer stem cells [99]. In addition, cancer stem cells from medulloblastoma were more sensitive to inhibition of the kinase Akt, which requires HSP90 for activity, than the cancer cells from the same tumour mass [100].

However, inhibition of HSP90 as a drug strategy is often associated with the compensatory upregulation of other molecular chaperones, especially HSP70, in cells treated with HSP90 inhibitors. Inhibition of HSP90 causes activation of HSF-1 that induces the expression of other members of the HSP family [101, 102]. While upregulation of other HSP has been associated with drug resistance to HSP90 inhibitors [103, 104], some researchers have used this fortuitous induction of other chaperones as a strategy to treat protein folding diseases such as Alzheimer’s disease [105] and as a mechanism to promote cytoprotection [106]. The most effective strategy, with respect to anti-cancer therapy, therefore may be the simultaneous inhibition of HSP90 and HSP70 [107] or even the inhibition of the heat shock response by direct inhibition of HSF-1 [108]. We and others have identified a number of small molecule inhibitors of HSP70 function in parasites, which may also have future potential as co-inhibitors of HSP70 in human cancers.

4.4 Future Prospects for HSP-Directed Drug Discovery in Africa

Despite extensive research into the function of HSP in cancer and parasitic diseases, there are still relatively few anti-HSP compounds that have made it to the market as drugs [109, 110, 111]. The most successful compound at present is 17-AAG, currently in clinical trials as an anti-cancer agent and also with potential as a treatment for parasite diseases demonstrated by in vitro studies. However, there is still great potential for drug discovery in this area, particularly as our fundamental knowledge of the structure and function of different HSP systems grows.

4.4.1 Identification of New Indigenous Compounds That Target HSP

A number of small molecules have been found by us and others to modulate the activity of the conserved HSP70 and HSP90 proteins from different organisms. What is striking is the number of these compounds that are either natural products or analogues of natural products. Natural products are a good source of compounds that are difficult to synthesise by traditional chemical methods and may also serve as the basis for rational drug design. Many natural compounds may exhibit activity as the parent compound and may be of value as scaffolds for the development of novel compounds. The diversity of South African flora and fauna has yielded many natural products that show anti-cancer [84, 112, 113] and anti-plasmodial activity [114] that have structural similarity to known HSP inhibitors [115, 116]. Therefore, the analysis of the effect of these indigenous compounds has the potential to identify novel modulators of chaperone function.

4.4.2 Evaluation of Co-chaperones as Drug Targets

Molecular chaperones function as part of multi-chaperone complexes, complexes which often include other proteins known as co-chaperones. Co-chaperones are a diverse group of proteins that modulate the function of and promote the interaction between the major molecular chaperones. The most well-known co-chaperones of both the HSP90 and HSP70 families are the HSP40 family and the tetratricopeptide repeat containing co-chaperone HOP. The central role played by co-chaperones in the modulation of the function of other chaperones means that these proteins may also be good drug targets.

HSP40s are the major co-chaperones in the HSP70-assisted protein folding process and act via regulation of the ATPase activity of HSP70. HSP40 are the largest and most diverse group of co-chaperones. This diversity is conserved across organisms; there are 49 HSP40 genes in humans, 43 in P. falciparum and 67 genes in T. brucei [46, 117, 118]. HSP40 proteins are classified as type I, II or III, depending on the degree of conservation of the functional motifs they contain, with respect to Escherichia coli (E. coli) DnaJ [119]. We have recently proposed an additional group, type IV HSP40, which, besides a few isoforms in humans and yeast, appears specific to malaria parasites [46]. The type and number of motifs contained in an HSP40 will govern its function, with most of the HSP70 chaperone interactions being modulated by type I HSP40s. More specific functions are likely to be mediated by type III or type IV HSP40s [120, 121]. HSP40 may prove to be the better chaperone drug target, as unlike HSP90 and HSP70 where the same chaperone is responsible for chaperoning numerous clients, many HSP40 are selective and will only bind a restricted number of proteins. This may allow for the preferential targeting of specific signalling pathways through the targeting of a single HSP40 isoform [46].

HOP is a co-chaperone that is involved in mediating interactions between HSP70 and HSP90. HOP acts as an adapter between the two chaperones and controls the transfer of protein substrates between the two systems. HOP is essential for the chaperone function of both Hsp70 and Hsp90 as part of the Hsp90 complex. Therefore, inhibition of HOP has the theoretical potential not only to inhibit complexed Hsp90 (the state of Hsp90 observed in cancerous cells) but also to facilitate the simultaneous dual inhibition of both Hsp90 and Hsp70, thereby preventing any redundancy between the two chaperone systems that may occur when these proteins are targeted individually. In addition, it is now apparent that HOP is also expressed by parasites, such as P. falciparum and T. cruzi. We and others are therefore in the process of characterising human and parasitic HOP as future potential drug targets [122, 123, 124, 125].

4.4.3 HSP as Biotechnological Tools in Drug Discovery

In addition to the well-described role as drug targets, there is also the potential to use molecular chaperones as tools in biotechnology. The protein folding and quality control functions of HSP can be harnessed to synthesise other drug targets for drug characterisation studies. The limiting factor for many drug development programmes is the availability of sufficient quantities of active, folded drug targets for use in drug characterisation studies. We have recently published on the use of co-expression of molecular chaperones for the synthesis of putative drug targets [126]. We were able to demonstrate the production of active, folded cyclohydrolase enzyme from P. falciparum for use in in vitro enzymatic assays for inhibitor characterisation. Similar techniques were used to successfully produce large quantities of other malarial drug targets, such as PfDXR [127, 128]. To the best of our knowledge, these publications are the first to demonstrate the use of a homologous chaperone–client system, where the drug target and the chaperone used to refold it are from the same organism (in this case, P. falciparum), for biotechnological production of a drug target. This research is ongoing and has great potential to develop a drug discovery platform technology in Africa.


  1. 1.
    Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181(96):223–230CrossRefGoogle Scholar
  2. 2.
    Hendrick JP, Hartl FU (1993) Molecular chaperone functions of heat-shock proteins. Annu Rev Biochem 62:349–384CrossRefGoogle Scholar
  3. 3.
    Ritossa FM, Vonborstel RC (1964) Chromosome puffs in Drosophila induced by ribonuclease. Science 145:513–514CrossRefGoogle Scholar
  4. 4.
    Li Z, Srivastava P (2004) Heat-shock proteins. Curr Protoc Immunol Appendix 1:Appendix 1TGoogle Scholar
  5. 5.
    Morimoto RI, Kline MP et al (1997) The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones. Essays Biochem 32:17–29Google Scholar
  6. 6.
    Dudek J, Benedix J et al (2009) Functions and pathologies of BiP and its interaction partners. Cell Mol Life Sci 66(9):1556–1569CrossRefGoogle Scholar
  7. 7.
    Palotai R, Szalay MS, Csermely P (2008) Chaperones as integrators of cellular networks: changes of cellular integrity in stress and diseases. IUBMB Life 60(1):10–18CrossRefGoogle Scholar
  8. 8.
    Fink AL (1999) Chaperone-mediated protein folding. Physiol Rev 79(2):425–449Google Scholar
  9. 9.
    Park HO, Craig EA (1991) Transcriptional regulation of a yeast HSP70 gene by heat shock factor and an upstream repression site-binding factor. Genes Dev 5(7):1299–1308CrossRefGoogle Scholar
  10. 10.
    Frydman J (2001) Folding of newly translated proteins in vivo: the role of molecular chaperones. Annu Rev Biochem 70:603–647CrossRefGoogle Scholar
  11. 11.
    Csermely P, Schnaider T et al (1998) The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review. Pharmacol Ther 79(2):129–168CrossRefGoogle Scholar
  12. 12.
    Krone PH, Sass JB (1994) HSP 90 alpha and HSP 90 beta genes are present in the zebrafish and are differentially regulated in developing embryos. Biochem Biophys Res Commun 204(2):746–752CrossRefGoogle Scholar
  13. 13.
    Terasawa K, Minami M, Minami Y (2005) Constantly updated knowledge of Hsp90. J Biochem 137(4):443–447CrossRefGoogle Scholar
  14. 14.
    Shonhai A, Maier AG et al (2011) Intracellular protozoan parasites of humans: the role of molecular chaperones in development and pathogenesis. Protein Pept Lett 18(2):143–157CrossRefGoogle Scholar
  15. 15.
    Chen B, Zhong D, Monteiro A (2006) Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms. BMC Genomics 7:156CrossRefGoogle Scholar
  16. 16.
    Rao R, Fiskus W et al (2008) HDAC6 inhibition enhances 17-AAG–mediated abrogation of hsp90 chaperone function in human leukemia cells. Blood 112(5):1886–1893CrossRefGoogle Scholar
  17. 17.
    Aoyagi S, Archer TK (2005) Modulating molecular chaperone Hsp90 functions through reversible acetylation. Trends Cell Biol 15(11):565–567CrossRefGoogle Scholar
  18. 18.
    Yang Y, Rao R et al (2008) Role of acetylation and extracellular location of heat shock protein 90α in tumor cell invasion. Cancer Res 68(12):4833–4842CrossRefGoogle Scholar
  19. 19.
    Martinez-Ruiz A, Villanueva L et al (2005) S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci USA 102(24):8525–8530CrossRefGoogle Scholar
  20. 20.
    Duval M, Le Boeuf F et al (2007) Src-mediated phosphorylation of Hsp90 in response to vascular endothelial growth factor (VEGF) is required for VEGF receptor-2 signaling to endothelial NO synthase. Mol Biol Cell 18(11):4659–4668CrossRefGoogle Scholar
  21. 21.
    Nemoto T, Sato N (1998) Oligomeric forms of the 90-kDa heat shock protein. Biochem J 330(2):989–995Google Scholar
  22. 22.
    Nemoto T, Sato N et al (1997) Domain structures and immunogenic regions of the 90-kDa heat-shock protein (HSP90). Probing with a library of anti-HSP90 monoclonal antibodies and limited proteolysis. J Biol Chem 272(42):26179–26187CrossRefGoogle Scholar
  23. 23.
    Hainzl O, Lapina MC et al (2009) The charged linker region is an important regulator of Hsp90 function. J Biol Chem 284(34):22559–22567CrossRefGoogle Scholar
  24. 24.
    Scheibel T, Siegmund HI et al (1999) The charged region of Hsp90 modulates the function of the N-terminal domain. Proc Natl Acad Sci USA 96(4):1297–1302CrossRefGoogle Scholar
  25. 25.
    Prodromou C, Roe SM et al (1997) Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone. Cell 90(1):65–75CrossRefGoogle Scholar
  26. 26.
    Grenert JP, Sullivan WP et al (1997) The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation. J Biol Chem 272(38):23843–23850CrossRefGoogle Scholar
  27. 27.
    Kumar R, Musiyenko A, Barik S (2003) The heat shock protein 90 of Plasmodium falciparum and antimalarial activity of its inhibitor, geldanamycin. Malar J 2:30CrossRefGoogle Scholar
  28. 28.
    Graefe SE, Wiesgigl M et al (2002) Inhibition of HSP90 in Trypanosoma cruzi induces a stress response but no stage differentiation. Eukaryot Cell 1(6):936–943CrossRefGoogle Scholar
  29. 29.
    Wayne N, Bolon DN (2007) Dimerization of Hsp90 is required for in vivo function. Design and analysis of monomers and dimers. J Biol Chem 282(48):35386–35395CrossRefGoogle Scholar
  30. 30.
    Brinker A, Scheufler C et al (2002) Ligand discrimination by TPR domains. Relevance and selectivity of EEVD-recognition in Hsp70 x Hop x Hsp90 complexes. J Biol Chem 277(22):19265–19275CrossRefGoogle Scholar
  31. 31.
    Odunuga OO, Hornby JA et al (2003) Tetratricopeptide repeat motif-mediated Hsc70-mSTI1 interaction. Molecular characterization of the critical contacts for successful binding and specificity. J Biol Chem 278(9):6896–6904CrossRefGoogle Scholar
  32. 32.
    Southworth DR, Agard DA (2011) Client-loading conformation of the Hsp90 molecular chaperone revealed in the Cryo-EM structure of the human Hsp90:Hop complex. Mol Cell 42(6):771–781CrossRefGoogle Scholar
  33. 33.
    Agashe VR, Hartl FU (2000) Roles of molecular chaperones in cytoplasmic protein folding. Semin Cell Dev Biol 11(1):15–25CrossRefGoogle Scholar
  34. 34.
    Modisakeng KW, Jiwaji M et al (2009) Isolation of a Latimeria menadoensis heat shock protein 70 (Lmhsp70) that has all the features of an inducible gene and encodes a functional molecular chaperone. Mol Genet Genomics 282(2):185–196CrossRefGoogle Scholar
  35. 35.
    Louw CA, Ludewig MH et al (2010) The Hsp70 chaperones of the Tritryps are characterized by unusual features and novel members. Parasitol Int 59(4):497–505CrossRefGoogle Scholar
  36. 36.
    Shonhai A, Boshoff A, Blatch GL (2007) The structural and functional diversity of Hsp70 proteins from Plasmodium falciparum. Protein Sci 16(9):1803–1818CrossRefGoogle Scholar
  37. 37.
    James P, Pfund C, Craig EA (1997) Functional specificity among Hsp70 molecular chaperones. Science 275(5298):387–389CrossRefGoogle Scholar
  38. 38.
    Flaherty KM, DeLuca-Flaherty C, McKay DB (1990) Three-dimensional structure of the ATPase fragment of a 70K heat-shock cognate protein. Nature 346(6285):623–628CrossRefGoogle Scholar
  39. 39.
    Wisniewska M, Karlberg T et al (2010) Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L/Hsp70-hom, HSPA2/Hsp70-2, HSPA6/Hsp70B′, and HSPA5/BiP/GRP78. PLoS One 5(1):e8625CrossRefGoogle Scholar
  40. 40.
    Wawrzynow A, Banecki B et al (1995) ATP hydrolysis is required for the DnaJ-dependent activation of DnaK chaperone for binding to both native and denatured protein substrates. J Biol Chem 270(33):19307–19311CrossRefGoogle Scholar
  41. 41.
    Karlin S, Brocchieri L (1998) Heat shock protein 70 family: multiple sequence comparisons, function, and evolution. J Mol Evol 47(5):565–577CrossRefGoogle Scholar
  42. 42.
    Cockburn IL, Pesce ER et al (2011) Screening for small molecule modulators of Hsp70 chaperone activity using protein aggregation suppression assays: inhibition of the plasmodial chaperone PfHsp70-1. Biol Chem 392(5):431–438CrossRefGoogle Scholar
  43. 43.
    Bakheet TM, Doig AJ (2009) Properties and identification of human protein drug targets. Bioinformatics 25(4):451–457CrossRefGoogle Scholar
  44. 44.
    Chiosis G, Neckers L (2006) Tumor selectivity of Hsp90 inhibitors: the explanation remains elusive. ACS Chem Biol 1(5):279–284CrossRefGoogle Scholar
  45. 45.
    Acharya P, Kumar R, Tatu U (2007) Chaperoning a cellular upheaval in malaria: heat shock proteins in Plasmodium falciparum. Mol Biochem Parasitol 153(2):85–94CrossRefGoogle Scholar
  46. 46.
    Botha M, Pesce ER, Blatch GL (2007) The Hsp40 proteins of Plasmodium falciparum and other apicomplexa: regulating chaperone power in the parasite and the host. Int J Biochem Cell Biol 39(10):1781–1803CrossRefGoogle Scholar
  47. 47.
    Banumathy G, Singh V et al (2003) Heat shock protein 90 function is essential for Plasmodium falciparum growth in human erythrocytes. J Biol Chem 278(20):18336–18345CrossRefGoogle Scholar
  48. 48.
    Pallavi R, Roy N et al (2010) Heat shock protein 90 as a drug target against protozoan infections: biochemical characterization of HSP90 from Plasmodium falciparum and Trypanosoma evansi and evaluation of its inhibitor as a candidate drug. J Biol Chem 285(49):37964–37975CrossRefGoogle Scholar
  49. 49.
    Edkins AL, Ludewig MH, Blatch GL (2004) A Trypanosoma cruzi heat shock protein 40 is able to stimulate the adenosine triphosphate hydrolysis activity of heat shock protein 70 and can substitute for a yeast heat shock protein 40. Int J Biochem Cell Biol 36(8):1585–1598CrossRefGoogle Scholar
  50. 50.
    Shonhai A, Boshoff A, Blatch GL (2005) Plasmodium falciparum heat shock protein 70 is able to suppress the thermosensitivity of an Escherichia coli DnaK mutant strain. Mol Genet Genomics 274(1):70–78CrossRefGoogle Scholar
  51. 51.
    Matambo TS, Odunuga OO et al (2004) Overproduction, purification, and characterization of the Plasmodium falciparum heat shock protein 70. Protein Expr Purif 33(2):214–222CrossRefGoogle Scholar
  52. 52.
    Ramya TN, Surolia N, Surolia A (2006) 15-Deoxyspergualin modulates Plasmodium falciparum heat shock protein function. Biochem Biophys Res Commun 348(2):585–592CrossRefGoogle Scholar
  53. 53.
    Bell SL, Chiang AN, Brodsky JL (2011) Expression of a malarial Hsp70 improves defects in chaperone-dependent activities in ssa1 mutant yeast. PLoS One 6(5):e20047CrossRefGoogle Scholar
  54. 54.
    Kumar N, Koski G et al (1991) Induction and localization of Plasmodium falciparum stress proteins related to the heat shock protein 70 family. Mol Biochem Parasitol 48(1):47–58CrossRefGoogle Scholar
  55. 55.
    Pesce ER, Acharya P et al (2008) The Plasmodium falciparum heat shock protein 40, Pfj4, associates with heat shock protein 70 and shows similar heat induction and localisation patterns. Int J Biochem Cell Biol 40(12):2914–2926CrossRefGoogle Scholar
  56. 56.
    Misra G, Ramachandran R (2009) Hsp70-1 from Plasmodium falciparum: protein stability, domain analysis and chaperone activity. Biophys Chem 142(1–3):55–64CrossRefGoogle Scholar
  57. 57.
    Shonhai A, Botha M et al (2008) Structure-function study of a Plasmodium falciparum Hsp70 using three dimensional modelling and in vitro analyses. Protein Pept Lett 15(10):1117–1125CrossRefGoogle Scholar
  58. 58.
    Evans CG, Chang L, Gestwicki JE (2010) Heat shock protein 70 (hsp70) as an emerging drug target. J Med Chem 53(12):4585–4602CrossRefGoogle Scholar
  59. 59.
    Pesce ER, Cockburn IL et al (2010) Malaria heat shock proteins: drug targets that chaperone other drug targets. Infect Disord Drug Targets 10(3):147–157CrossRefGoogle Scholar
  60. 60.
    Shonhai A (2010) Plasmodial heat shock proteins: targets for chemotherapy. FEMS Immunol Med Microbiol 58(1):61–74CrossRefGoogle Scholar
  61. 61.
    Nadeau K, Nadler SG et al (1994) Quantitation of the interaction of the immunosuppressant deoxyspergualin and analogs with Hsc70 and Hsp90. Biochemistry 33(9):2561–2567CrossRefGoogle Scholar
  62. 62.
    Brodsky JL (1999) Selectivity of the molecular chaperone-specific immunosuppressive agent 15-deoxyspergualin: modulation of Hsc70 ATPase activity without compromising DnaJ chaperone interactions. Biochem Pharmacol 57(8):877–880CrossRefGoogle Scholar
  63. 63.
    Nadler SG, Dischino DD et al (1998) Identification of a binding site on Hsc70 for the immunosuppressant 15-deoxyspergualin. Biochem Biophys Res Commun 253(1):176–180CrossRefGoogle Scholar
  64. 64.
    Fewell SW, Smith CM et al (2004) Small molecule modulators of endogenous and co-chaperone-stimulated Hsp70 ATPase activity. J Biol Chem 279(49):51131–51140CrossRefGoogle Scholar
  65. 65.
    Huryn DM, Brodsky JL et al (2011) Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators. Proc Natl Acad Sci USA 108(17):6757–6762CrossRefGoogle Scholar
  66. 66.
    Wright CM, Chovatiya RJ et al (2008) Pyrimidinone-peptoid hybrid molecules with distinct effects on molecular chaperone function and cell proliferation. Bioorg Med Chem 16(6):3291–3301CrossRefGoogle Scholar
  67. 67.
    Chiang AN, Valderramos JC et al (2009) Select pyrimidinones inhibit the propagation of the malarial parasite, Plasmodium falciparum. Bioorg Med Chem 17(4):1527–1533CrossRefGoogle Scholar
  68. 68.
    Botha M, Chiang AN et al (2011) Plasmodium falciparum encodes a single cytosolic type I Hsp40 that functionally interacts with Hsp70 and is upregulated by heat shock. Cell Stress Chaperones 16(4):389–401CrossRefGoogle Scholar
  69. 69.
    Wisen S, Bertelsen EB et al (2010) Binding of a small molecule at a protein-protein interface regulates the chaperone activity of hsp70-hsp40. ACS Chem Biol 5(6):611–622CrossRefGoogle Scholar
  70. 70.
    Bonifazi EL, Rios-Luci C et al (2010) Antiproliferative activity of synthetic naphthoquinones related to lapachol. First synthesis of 5-hydroxylapachol. Bioorg Med Chem 18(7):2621–2630CrossRefGoogle Scholar
  71. 71.
    Pérez-Sacau E, Estévez-Braun A et al (2005) Antiplasmodial activity of naphthoquinones related to lapachol and beta-lapachone. Chem Biodivers 2(2):264–274CrossRefGoogle Scholar
  72. 72.
    Guiguemde WA, Shelat AA et al (2010) Chemical genetics of Plasmodium falciparum. Nature 465(7296):311–315CrossRefGoogle Scholar
  73. 73.
    Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5(10):761–772CrossRefGoogle Scholar
  74. 74.
    Buchner J (1999) Hsp90 & Co. – a holding for folding. Trends Biochem Sci 24(4):136–141CrossRefGoogle Scholar
  75. 75.
    Zhang H, Burrows F (2004) Targeting multiple signal transduction pathways through inhibition of Hsp90. J Mol Med 82(8):488–499CrossRefGoogle Scholar
  76. 76.
    Odunuga OO, Longshaw VM, Blatch GL (2004) Hop: more than an Hsp70/Hsp90 adaptor protein. Bioessays 26(10):1058–1068CrossRefGoogle Scholar
  77. 77.
    Kamal A, Thao L et al (2003) A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 425(6956):407–410CrossRefGoogle Scholar
  78. 78.
    Onuoha SC, Mukund SR et al (2007) Mechanistic studies on Hsp90 inhibition by ansamycin derivatives. J Mol Biol 372(2):287–297CrossRefGoogle Scholar
  79. 79.
    Taldone T, Gozman A et al (2008) Targeting Hsp90: small-molecule inhibitors and their clinical development. Curr Opin Pharmacol 8(4):370–374CrossRefGoogle Scholar
  80. 80.
    Jensen MR, Schoepfer J et al (2008) NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models. Breast Cancer Res 10(2):R33CrossRefGoogle Scholar
  81. 81.
    Tsutsumi S, Scroggins B et al (2008) A small molecule cell-impermeant Hsp90 antagonist inhibits tumor cell motility and invasion. Oncogene 27(17):2478–2487CrossRefGoogle Scholar
  82. 82.
    Sydor JR, Normant E et al (2006) Development of 17-allylamino-17-demethoxygeldanamycin hydroquinone hydrochloride (IPI-504), an anti-cancer agent directed against Hsp90. Proc Natl Acad Sci USA 103(46):17408–17413CrossRefGoogle Scholar
  83. 83.
    Donnelly A, Blagg BS (2008) Novobiocin and additional inhibitors of the Hsp90 C-terminal nucleotide-binding pocket. Curr Med Chem 15(26):2702–2717CrossRefGoogle Scholar
  84. 84.
    van der Merwe E, Huang D et al (2008) The synthesis and anticancer activity of selected diketopiperazines. Peptides 29(8):1305–1311CrossRefGoogle Scholar
  85. 85.
    Bisi-Johnson MA, Obi CL et al (2011) Evaluation of the antibacterial and anticancer activities of some South African medicinal plants. BMC Complement Altern Med 11:14CrossRefGoogle Scholar
  86. 86.
    Eustace BK, Sakurai T et al (2004) Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat Cell Biol 6(6):507–514CrossRefGoogle Scholar
  87. 87.
    Becker B, Multhoff G et al (2004) Induction of Hsp90 protein expression in malignant melanomas and melanoma metastases. Exp Dermatol 13(1):27–32CrossRefGoogle Scholar
  88. 88.
    Sidera K, Samiotaki M et al (2004) Involvement of cell surface HSP90 in cell migration reveals a novel role in the developing nervous system. J Biol Chem 279(44):45379–45388CrossRefGoogle Scholar
  89. 89.
    Sims JD, McCready J, Jay DG (2011) Extracellular heat shock protein (Hsp)70 and Hsp90α assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS One 6(4):e18848CrossRefGoogle Scholar
  90. 90.
    Lawson JC, Blatch GL, Edkins AL (2009) Cancer stem cells in breast cancer and metastasis. Breast Cancer Res Treat 118(2):241–254CrossRefGoogle Scholar
  91. 91.
    Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124(6):1111–1115CrossRefGoogle Scholar
  92. 92.
    Dalerba P, Cho RW, Clarke MF (2007) Cancer stem cells: models and concepts. Annu Rev Med 58:267–284CrossRefGoogle Scholar
  93. 93.
    Burger PE, Gupta R et al (2009) High aldehyde dehydrogenase activity: a novel functional marker of murine prostate stem/progenitor cells. Stem Cells 27(9):2220–2228CrossRefGoogle Scholar
  94. 94.
    Ma S, Lee TK et al (2008) CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27(12):1749–1758CrossRefGoogle Scholar
  95. 95.
    Glinsky GV (2007) Stem cell origin of death-from-cancer phenotypes of human prostate and breast cancers. Stem Cell Rev 3(1):79–93CrossRefGoogle Scholar
  96. 96.
    Prinsloo E, Setati MM et al (2009) Chaperoning stem cells: a role for heat shock proteins in the modulation of stem cell self-renewal and differentiation? Bioessays 31(4):370–377CrossRefGoogle Scholar
  97. 97.
    Kim HL, Cassone M et al (2008) HIF-1alpha and STAT3 client proteins interacting with the cancer chaperone Hsp90: therapeutic considerations. Cancer Biol Ther 7(1):10–14Google Scholar
  98. 98.
    Setati MM, Prinsloo E et al (2010) Leukemia inhibitory factor promotes Hsp90 association with STAT3 in mouse embryonic stem cells. IUBMB Life 62(1):61–66Google Scholar
  99. 99.
    Sauvageot CM, Weatherbee JL et al (2008) Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro Oncol 11(2):109–121CrossRefGoogle Scholar
  100. 100.
    Hambardzumyan D, Becher OJ et al (2008) PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo. Genes Dev 22(4):436–448CrossRefGoogle Scholar
  101. 101.
    Ali A, Bharadwaj S et al (1998) HSP90 interacts with and regulates the activity of heat shock factor 1 in Xenopus oocytes. Mol Cell Biol 18(9):4949–4960Google Scholar
  102. 102.
    Conde R, Belak ZR et al (2009) Modulation of Hsf1 activity by novobiocin and geldanamycin. Biochem Cell Biol 87(6):845–851CrossRefGoogle Scholar
  103. 103.
    McCollum AK, Teneyck CJ et al (2006) Up-regulation of heat shock protein 27 induces resistance to 17-allylamino-demethoxygeldanamycin through a glutathione-mediated mechanism. Cancer Res 66(22):10967–10975CrossRefGoogle Scholar
  104. 104.
    McCollum AK, Lukasiewicz KB et al (2008) Cisplatin abrogates the geldanamycin-induced heat shock response. Mol Cancer Ther 7(10):3256–3264CrossRefGoogle Scholar
  105. 105.
    Nagai Y, Fujikake N et al (2010) Induction of molecular chaperones as a therapeutic strategy for the polyglutamine diseases. Curr Pharm Biotechnol 11(2):188–197CrossRefGoogle Scholar
  106. 106.
    Westerheide SD, Bosman JD et al (2004) Celastrols as inducers of the heat shock response and cytoprotection. J Biol Chem 279(53):56053–56060CrossRefGoogle Scholar
  107. 107.
    Massey AJ, Williamson DS et al (2010) A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol 66(3):535–545CrossRefGoogle Scholar
  108. 108.
    Whitesell L, Lindquist S (2009) Inhibiting the transcription factor HSF1 as an anticancer strategy. Expert Opin Ther Targets 13(4):469–478CrossRefGoogle Scholar
  109. 109.
    Trepel J, Mollapour M et al (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10(8):537–549CrossRefGoogle Scholar
  110. 110.
    Wang Y, Trepel JB et al (2010) STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr Opin Investig Drugs 11(12):1466–1476Google Scholar
  111. 111.
    Kim YS, Alarcon SV et al (2009) Update on Hsp90 inhibitors in clinical trial. Curr Top Med Chem 9(15):1479–1492CrossRefGoogle Scholar
  112. 112.
    Brauns SC, Dealtry G et al (2005) Caspase-3 activation and induction of PARP cleavage by cyclic dipeptide cyclo(Phe-Pro) in HT-29 cells. Anticancer Res 25(6B):4197–4202Google Scholar
  113. 113.
    Brauns SC, Milne P et al (2004) Selected cyclic dipeptides inhibit cancer cell growth and induce apoptosis in HT-29 colon cancer cells. Anticancer Res 24(3a):1713–1719Google Scholar
  114. 114.
    Afolayan AF, Mann MG et al (2009) Antiplasmodial halogenated monoterpenes from the marine red alga Plocamium cornutum. Phytochemistry 70(5):597–600CrossRefGoogle Scholar
  115. 115.
    Afolayan AF, Bolton JJ et al (2008) Fucoxanthin, tetraprenylated toluquinone and toluhydroquinone metabolites from Sargassum heterophyllum inhibit the in vitro growth of the malaria parasite Plasmodium falciparum. Z Naturforsch C 63(11–12):848–852Google Scholar
  116. 116.
    Antunes EM, Beukes DR et al (2004) Cytotoxic pyrroloiminoquinones from four new species of South African latrunculid sponges. J Nat Prod 67(8):1268–1276CrossRefGoogle Scholar
  117. 117.
    Kampinga HH, Hageman J et al (2009) Guidelines for the nomenclature of the human heat shock proteins. Cell Stress Chaperones 14(1):105–111CrossRefGoogle Scholar
  118. 118.
    Louw CA, Ludewig MH, Blatch GL (2010) Overproduction, purification and characterisation of Tbj1, a novel Type III Hsp40 from Trypanosoma brucei, the African sleeping sickness parasite. Protein Expr Purif 69(2):168–177CrossRefGoogle Scholar
  119. 119.
    Cheetham ME, Caplan AJ (1998) Structure, function and evolution of DnaJ: conservation and adaptation of chaperone function. Cell Stress Chaperones 3(1):28–36CrossRefGoogle Scholar
  120. 120.
    Hennessy F, Boshoff A, Blatch GL (2005) Rational mutagenesis of a 40 kDa heat shock protein from Agrobacterium tumefaciens identifies amino acid residues critical to its in vivo function. Int J Biochem Cell Biol 37(1):177–191CrossRefGoogle Scholar
  121. 121.
    Hennessy F, Cheetham ME et al (2000) Analysis of the levels of conservation of the J domain among the various types of DnaJ-like proteins. Cell Stress Chaperones 5(4):347–358CrossRefGoogle Scholar
  122. 122.
    Walsh N, Larkin A et al (2011) RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation. Cancer Lett 306(2):180–189CrossRefGoogle Scholar
  123. 123.
    Longshaw VM, Chapple JP et al (2004) Nuclear translocation of the Hsp70/Hsp90 organizing protein mSTI1 is regulated by cell cycle kinases. J Cell Sci 117(Pt 5):701–710CrossRefGoogle Scholar
  124. 124.
    Longshaw VM, Baxter M et al (2009) Knockdown of the co-chaperone Hop promotes extranuclear accumulation of Stat3 in mouse embryonic stem cells. Eur J Cell Biol 88(3):153–166CrossRefGoogle Scholar
  125. 125.
    Daniel S, Bradley G et al (2008) Nuclear translocation of the phosphoprotein Hop (Hsp70/Hsp90 organizing protein) occurs under heat shock, and its proposed nuclear localization signal is involved in Hsp90 binding. Biochim Biophys Acta 1783(6):1003–1014CrossRefGoogle Scholar
  126. 126.
    Stephens LL, Shonhai A, Blatch GL (2011) Co-expression of the Plasmodium falciparum molecular chaperone, PfHsp70, improves the heterologous production of the antimalarial drug target GTP cyclohydrolase I, PfGCHI. Protein Expr Purif 77(2):159–165CrossRefGoogle Scholar
  127. 127.
    Bodill T, Conibear AC et al (2011) Synthesis and evaluation of phosphonated N-heteroarylcarboxamides as DOXP-reductoisomerase (DXR) inhibitors. Bioorg Med Chem 19(3):1321–1327CrossRefGoogle Scholar
  128. 128.
    Goble JL, Adendorff MR et al (2010) The malarial drug target Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (PfDXR): development of a 3-D model for identification of novel, structural and functional features and for inhibitor screening. Protein Pept Lett 17(1):109–120CrossRefGoogle Scholar

Copyright information

© Springer Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry, Microbiology and BiotechnologyRhodes UniversityGrahamstownSouth Africa

Personalised recommendations