The endoplasmic reticulum protein folding factory and its chaperones: New targets for drug discovery?

Institute of Cancer Research, London, UK.
British Journal of Pharmacology (Impact Factor: 4.99). 10/2010; 162(2):328-45. DOI: 10.1111/j.1476-5381.2010.01064.x
Source: PubMed

ABSTRACT Cytosolic heat shock proteins have received significant attention as emerging therapeutic targets. Much of this excitement has been triggered by the discovery that HSP90 plays a central role in the maintenance and stability of multifarious oncogenic membrane receptors and their resultant tyrosine kinase activity. Numerous studies have dealt with the effects of small molecules on chaperone- and stress-related pathways of the endoplasmic reticulum (ER). However, unlike cytosolic chaperones, relatively little emphasis has been placed upon translational avenues towards targeting of the ER for inhibition of folding/secretion of disease-promoting proteins. Here, we summarise existing small molecule inhibitors and potential future targets of ER chaperone-mediated inhibition. Client proteins of translational relevance in disease treatment are outlined, alongside putative future disease treatment modalities based on ER-centric targeted therapies. Particular attention is paid to cancer and autoimmune disorders via the effects of the GRP94 inhibitor geldanamycin and its population of client proteins, overloading of the unfolded protein response, and inhibition of members of the IL-12 family of cytokines by celecoxib and non-coxib analogues.

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Available from: Koen Vandenbroeck, Jan 13, 2015
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    • "E-mail: cells or are integrated into cell membranes (Roth et al., 2003, 2010; Trombetta and Parodi, 2003). Studies involving the use of GI/GII inhibitors have shown a substantial reduction in cell proliferation/migration (Pili et al., 1995) and incorporation of incorrectly folded proteins into the cell membranes (Chapel et al., 2007), prompting their use as drugs to curtail cell proliferation and migration in diseases such as cancer, viral infection, and diabetes (Pili et al., 1995; Asano, 2003; Hwu et al., 2003; Chapel et al., 2007; van de Laar, 2008; McLaughlin and Vandenbroeck, 2011). Given the importance of the GII enzyme in cell physiology, little is known about its expression in various tissues, including brain tissues, even though its presence in the brain was first reported in 1979 (Scher and Waechter, 1979; Tulsiani et al., 1990). "
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    ABSTRACT: α-Glucosidase II (GII), a resident of endoplasmic reticulum (ER) and an important enzyme in the folding of nascent glycoproteins, is heterodimeric, consisting of α (GIIα) and β (GIIβ) subunits. The catalytic GIIα subunit, with the help of mannose 6-phosphate receptor homology domain of GIIβ, sequentially hydrolyzes two α1-3-linked glucose residues in the second step of N-linked oligosaccharide-mediated protein folding. The soluble GIIα subunit is retained in the ER through its interaction with the HDEL-containing GIIβ subunit. N-glycosylation and correct protein folding are crucial for protein stability and trafficking and cell surface expression of several proteins in the brain. Alterations in N-glycosylation lead to abnormalities in neuronal migration and mental retardation, various neurodegenerative diseases, and invasion of malignant gliomas. Inhibitors of GII are used to inhibit cell proliferation and migration in a variety of different pathologies, such as viral infection, cancer, and diabetes. Despite the widespread use of GIIα inhibitory drugs and the role of GIIα in brain function, little is known about its expression in brain and other tissues. Here, we report generation of a highly specific chicken antibody to the GIIα subunit and its characterization by Western blotting and immunoprecipitation using cerebral cortical extracts. By using this antibody, we showed that the GIIα protein is highly expressed in testis, kidney, and lung, with the lowest amount in heart. GIIα polypeptide levels in whole brain were comparable to those in spleen. However, a higher expression of GIIα protein was detected in the cerebral cortex, reflecting its continuous requirement in correct folding of cell surface proteins. © 2014 Wiley Periodicals, Inc.
    Journal of Neuroscience Research 01/2015; 93(1). DOI:10.1002/jnr.23470 · 2.73 Impact Factor
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    • "This discovery of a link between ER stress and disease onset indicates that unfolded proteins play a role in the etiology of many of the most prevalent diseases. It has been suggested that therapeutic drug targeting and other interventions aimed at disrupting the ER stress cycle in such diseases would provide a useful treatment strategy [25] [26] [27]. Here we review recent evidence for the involvement of ER stress in PD. "
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    ABSTRACT: Endoplasmic reticulum (ER) stress has been known to be involved in the pathogenesis of various diseases, particularly neurodegenerative disorders such as Parkinson's disease (PD). We previously identified the human ubiquitin ligase HRD1 that is associated with protection against ER stress and its associated apoptosis. HRD1 promotes the ubiquitination and degradation of Parkin-associated endothelin receptor-like receptor (Pael-R), an ER stress inducer and causative factor of familial PD, thereby preventing Pael-R-induced neuronal cell death. Moreover, upregulation of HRD1 by the antiepileptic drug zonisamide suppresses 6-hydroxydopamine-induced neuronal cell death. We review recent progress in the studies on the mechanism of ER stress-induced neuronal death related to PD, particularly focusing on the involvement of HRD1 in the prevention of neuronal death as well as a potential therapeutic approach for PD based on the upregulation of HRD1.
    Oxidative medicine and cellular longevity 04/2013; 2013:239854. DOI:10.1155/2013/239854 · 3.36 Impact Factor
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    • "On the other hand, we have also reported the isolation from Melia azedarach L. of the limonoid 1-cin- namoyl-3,11-dihydroxymeliacarpin (CDM) which might be affecting a cellular factor involved in the transport of viral glycoproteins [11]. The integrity of the viral glycoproteins is critical for virion entry and/or assembly, therefore, cellular factors implicated in vesicular transport, membrane trafficking and glycoprotein processing acquired much relevance as potential targets for novel antiviral drugs [12]. Otherwise, we have successfully applied a new strategy to achieve sterol analogues with a high structural diversity by a simple and fast procedure [13] [14]. "
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    ABSTRACT: The need to develop novel antiviral agents encouraged us to assess the antiviral activity of synthetic sterol analogues with a diamide side chains. Cytotoxicity and antiviral activity of a family of azasterol previously synthesized was evaluated against herpes simplex virus 1 (HSV-1) (KOS and B2006) and vesicular stomatitis virus (VSV). This family of compounds was extended by the synthesis of novel analogs using an Ugi multicomponent reaction and their ability to inhibit viral multiplication was also evaluated. The results show that some of the compounds tested exert an antiviral activity. Besides, the effect of the azasterols on the intracellular localization of viral glycoproteins was examined. Strikingly, alteration on the glycoprotein D (gD) of HSV-1 fluorescence pattern was observed with both the antiherpetic compounds and the inactive azasterols.
    Biochemical and Biophysical Research Communications 09/2012; 427(1):107-12. DOI:10.1016/j.bbrc.2012.09.019 · 2.28 Impact Factor
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