scholarly journals Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

2020 ◽  
Vol 11 ◽  
Author(s):  
José Miguel Vela
Keyword(s):  
Stress Response ◽  
Viral Replication ◽  
Er Stress ◽  
Host Cell ◽  
Drug Repurposing ◽  
Host Protein ◽  
Unique Challenge ◽  
Sigma 1 Receptor ◽  
Sigma 1

Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

Influenza A viruses balance ER stress with host protein synthesis shutoff

2021 ◽  
Vol 118 (36) ◽  
pp. e2024681118
Author(s):  
Beryl Mazel-Sanchez ◽  
Justyna Iwaszkiewicz ◽  
Joao P. P. Bonifacio ◽  
Filo Silva ◽  
Chengyue Niu ◽  
...  
Keyword(s):  
Viral Replication ◽  
Er Stress ◽  
Host Cell ◽  
Messenger Rna ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Host Protein ◽  
Stress Induction ◽  
Nonstructural Protein 1

Excessive production of viral glycoproteins during infections poses a tremendous stress potential on the endoplasmic reticulum (ER) protein folding machinery of the host cell. The host cell balances this by providing more ER resident chaperones and reducing translation. For viruses, this unfolded protein response (UPR) offers the potential to fold more glycoproteins. We postulated that viruses could have developed means to limit the inevitable ER stress to a beneficial level for viral replication. Using a relevant human pathogen, influenza A virus (IAV), we first established the determinant for ER stress and UPR induction during infection. In contrast to a panel of previous reports, we identified neuraminidase to be the determinant for ER stress induction, and not hemagglutinin. IAV relieves ER stress by expression of its nonstructural protein 1 (NS1). NS1 interferes with the host messenger RNA processing factor CPSF30 and suppresses ER stress response factors, such as XBP1. In vivo viral replication is increased when NS1 antagonizes ER stress induction. Our results reveal how IAV optimizes glycoprotein expression by balancing folding capacity.

Abstract 281: Sigma-1 Receptor Dependent Pathway for a Protective Endoplasmic Reticulum Stress Response in Cardiomyocytes

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Shafiul Alam ◽  
A. Wayne Orr ◽  
Christopher B. Pattillo ◽  
Md. Shenuarin Bhuiyan
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Nuclear Transport ◽  
Neuronal Cell ◽  
Neonatal Rat ◽  
Mouse Heart ◽  
Sigma 1 Receptor ◽  
Er Stress Response ◽  
Chop Expression ◽  
Sigma 1

Rationale: We recently reported that Sigma 1 receptor (Sigmar1) is a molecular chaperone protein highly expressed in the heart. Studies involving different cancer and neuronal cell lines indicated Sigmar1 resides in the mitochondrion-associated ER membrane (MAM). However, the subcellular localization of Sigmar1 and the molecular function in ER-stress remains unknown in cardiomyocytes. Here we describe a function for Sigmar1 as an effector of an adaptive ER stress response. Objective: The objective of this study was to elucidate functional roles of Simgar1 in ER-stress in cardiomyocytes. Methods and Results: Subcellular fractionation of the mouse heart showed extensive localization of Sigmar1 in the MAM and mitochondrial fraction. To define the function in an ER-stress response, we used small interfering RNA-mediated Sigmar1 knockdown and adenovirus-mediated overexpression in cultured neonatal rat ventricular cardiomyocytes. We treated with tunicamycin to induce ER stress. In cardiomyocytes, tunicamycin increased C/EBP-homologous protein (CHOP) expression; Sigmar1 overexpression significantly decreased the CHOP expression. We found that Sigmar1 overexpression was sufficient to activate the nuclear transport of spliced X-box binding protein 1 (Xbp1s) with minimal effects in other adaptive ER stress proteins. Sigmar1 knockdown decreased the nuclear transport of Xbp1s, increased the expression of nuclear CHOP and significantly increased LDH release. We also observed significant Sigmar1 expression dependent increases in mitochondrial respiration in cardiomyocytes under ER stress. Hence, Sigmar1 can function inside the cell during disease remodeling to augment ER function and protect through a mechanism involving regulation of Xbp1s. Conclusions: Sigmar1 is an essential component of the adaptive ER stress response in cardiomyocytes. Sigmar1 can regulate ER-stress induced CHOP expression by activating XBP1s signaling in cardiomyocytes. Therefore, Sigmar1 residing at the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-response signaling between the ER and mitochondria.

scholarly journals Sigma-1 Receptor Promotes Mitochondrial Bioenergetics by Orchestrating ER Ca2+ Leak during Early ER Stress

Metabolites ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 422
Author(s):  
Zhanat Koshenov ◽  
Furkan E. Oflaz ◽  
Martin Hirtl ◽  
Johannes Pilic ◽  
Olaf A. Bachkoenig ◽  
...  
Keyword(s):  
Er Stress ◽  
Energy Demand ◽  
Molecular Mechanisms ◽  
High Energy ◽  
Human Neuroblastoma Cell ◽  
Mitochondrial Bioenergetics ◽  
Dependent Manner ◽  
Human Neuroblastoma ◽  
Sigma 1 Receptor ◽  
Sigma 1

The endoplasmic reticulum (ER) is a complex, multifunctional organelle of eukaryotic cells and responsible for the trafficking and processing of nearly 30% of all human proteins. Any disturbance to these processes can cause ER stress, which initiates an adaptive mechanism called unfolded protein response (UPR) to restore ER functions and homeostasis. Mitochondrial ATP production is necessary to meet the high energy demand of the UPR, while the molecular mechanisms of ER to mitochondria crosstalk under such stress conditions remain mainly enigmatic. Thus, better understanding the regulation of mitochondrial bioenergetics during ER stress is essential to combat many pathologies involving ER stress, the UPR, and mitochondria. This article investigates the role of Sigma-1 Receptor (S1R), an ER chaperone, has in enhancing mitochondrial bioenergetics during early ER stress using human neuroblastoma cell lines. Our results show that inducing ER stress with tunicamycin, a known ER stressor, greatly enhances mitochondrial bioenergetics in a time- and S1R-dependent manner. This is achieved by enhanced ER Ca2+ leak directed towards mitochondria by S1R during the early phase of ER stress. Our data point to the importance of S1R in promoting mitochondrial bioenergetics and maintaining balanced H2O2 metabolism during early ER stress.

At the Crossing of ER Stress and MAMs: A Key Role of Sigma-1 Receptor?

2019 ◽  
pp. 699-718 ◽  
Author(s):  
Benjamin Delprat ◽  
Lucie Crouzier ◽  
Tsung-Ping Su ◽  
Tangui Maurice
Keyword(s):  
Er Stress ◽  
Sigma 1 Receptor ◽  
Sigma 1

scholarly journals Contrasting Function of Structured N-Terminal and Unstructured C-Terminal Segments of Mycobacterium tuberculosis PPE37 Protein

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Javeed Ahmad ◽  
Aisha Farhana ◽  
Rita Pancsa ◽  
Simran Kaur Arora ◽  
Alagiri Srinivasan ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Mycobacterium Tuberculosis ◽  
Host Cell ◽  
Terminal Segment ◽  
Host Protein ◽  
Host Cells ◽  
Productive Infection ◽  
Disordered Proteins ◽  
Intrinsically Disordered

ABSTRACT Pathogens frequently employ eukaryotic linear motif (ELM)-rich intrinsically disordered proteins (IDPs) to perturb and hijack host cell networks for a productive infection. Mycobacterium tuberculosis has a relatively high percentage of IDPs in its proteome, the significance of which is not known. The Mycobacterium-specific PE-PPE protein family has several members with unusually high levels of structural disorder and disorder-promoting Ala/Gly residues. PPE37 protein, a member of this family, carries an N-terminal PPE domain capable of iron binding, two transmembrane domains, and a disordered C-terminal segment harboring ELMs and a eukaryotic nuclear localization signal (NLS). PPE37, expressed as a function of low iron stress, was cleaved by M. tuberculosis protease into N- and C-terminal segments. A recombinant N-terminal segment (P37N) caused proliferation and differentiation of monocytic THP-1 cells, into CD11c, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin)-positive semimature dendritic cells exhibiting high interleukin-10 (IL-10) but negligible IL-12 and also low tumor necrosis factor alpha (TNF-α) secretion—an environment suitable for maintaining tolerogenic immune cells. The C-terminal segment entered the macrophage nucleus and induced caspase-3-dependent apoptosis of host cells. Mice immunized with recombinant PPE37FL and PPE37N evoked strong anti-inflammatory response, validating the in vitro immunostimulatory effect. Analysis of the IgG response of PPE37FL and PPE37N revealed significant immunoreactivities in different categories of TB patients, viz. pulmonary TB (PTB) and extrapulmonary TB (EPTB), vis-a-vis healthy controls. These results support the role of IDPs in performing contrasting activities to modulate the host processes, possibly through molecular mimicry and cross talk in two spatially distinct host environments which may likely aid M. tuberculosis survival and pathogenesis. IMPORTANCE To hijack the human host cell machinery to enable survival inside macrophages, the pathogen Mycobacterium tuberculosis requires a repertoire of proteins that can mimic host protein function and modulate host cell machinery. Here, we have shown how a single protein can play multiple functions and hijack the host cell for the benefit of the pathogen. Full-length membrane-anchored PPE37 protein is cleaved into N- and C-terminal domains under iron-depleted conditions. The N-terminal domain facilitates the propathogen semimature tolerogenic state of dendritic cells, whereas the C-terminal segment is localized into host cell nucleus and induces apoptosis. The immune implications of these in vitro observations were assessed and validated in mice and also human TB patients. This study presents novel mechanistic insight adopted by M. tuberculosis to survive inside host cells.

Preliminary in vitro assessment of pharmacokinetic drug-drug interactions of EST64401 and EST64514, two sigma-1 receptor antagonists

Xenobiotica ◽  
2020 ◽  
pp. 1-40
Author(s):  
Raquel F. Reinoso ◽  
Sandra Yeste ◽  
Eva Ayet ◽  
María José Pretel ◽  
Ariadna Balada ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Receptor Antagonists ◽  
Sigma 1 Receptor ◽  
Sigma 1 ◽  
In Vitro Assessment ◽  
Pharmacokinetic Drug

scholarly journals Dengue virus-induced ER stress is required for autophagy activation, viral replication, and pathogenesis both in vitro and in vivo

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Ying-Ray Lee ◽  
Szu-Han Kuo ◽  
Ching-Yen Lin ◽  
Po-Jung Fu ◽  
Yee-Shin Lin ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Viral Replication ◽  
Er Stress

Abstract B119: Blocking metabolic stress response with genetic knockdown and selective ligands of sigma-1 receptor in cancer cells

2015 ◽  
Author(s):  
Gianluca Civenni ◽  
Celeste De Monte ◽  
Federica Sereni ◽  
Sara Allegrini ◽  
Roberto Bosotti ◽  
...  
Keyword(s):  
Stress Response ◽  
Cancer Cells ◽  
Metabolic Stress ◽  
Sigma 1 Receptor ◽  
Selective Ligands ◽  
Sigma 1

Secondary Bortezomib-Resistance Is Characterized by Upregulation of Proteasomal Subunits and Their Insufficient Inhibition by Bortezomib, Which Can Be Overcome by Alternative Proteasome Inhibitors Combined with Induction of the ER Stress Response.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2583-2583
Author(s):  
Thomas Ruckrich ◽  
Jeannette Gogel ◽  
Marianne Kraus ◽  
Huib Ovaa ◽  
Christoph Driessen
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Proteasome Inhibitors ◽  
Cytotoxic Drugs ◽  
Proteasome Activity ◽  
Intact Cells ◽  
Secondary Resistance ◽  
Er Stress Response ◽  
Proteolytic Pathways

Abstract Resistance towards proteasome inhibition by Bortezomib (Velcade®) represents a challenge for myeloma therapy. Its biology has not yet been characterized in detail. We have demonstrated that Bortezomib-sensitive malignant haematopoetic cells can acquire secondary resistance to Bortezomib in vitro. We here present the first analysis of proteasome biology and activity, alternative proteolytic pathways, ubiquitin-specific proteases (USP) and the ER stress response (unfolded protein response, UPR) upstream of the proteasome, as well as in vitro cytotoxicity of conventional cytotoxic drugs, alternative proteasome inhibitors and agents that target the UPR in Bortezomib-resistant (BR) cells, compared to wild type (WT) controls. BR cells had higher activities of all subunits of the constitutive and the immunoproteasome, as deferred from turnover of fluorogenic substrates as well as affinity-labelling of active proteasome subunits in intact cells. This was mirrored by increased levels of proteasomal β1 and β2, but especially β5 polypeptides, implicating a homeostatic system that senses and corrects low proteasome activity in cells chronically exposed to Bortezomib. While the vinylsulfone-type proteasome inhibitor NLVS abrogated detectable proteasome activity in both BR and WT cells, Bortezomib at therapeutic concentrations eliminated proteasomal β1 and β5-type activity only in WT cells, while BR cells retained residual activity. These changes in proteasome biology appear to be the molecular hallmark of required Bortezomib resistance, since no changes were observed between WT and BR cells in alternative cytosolic or lysosomal proteolytic pathways, UPR activity as well as the gross activity pattern of USP. As expected, this translated into sensitivity against cytotoxic drugs in vitro: BR cells were less sensitive towards alternative proteasome inhibitors. However, while the IC50 for pan-proteasome inhibitors was only roughly doubled in BR cells, it was nearly tenfold elevated for the β5-preferring vinylsulfone inhibitor NLVS. By contrast, sensitivity towards anthracyclines or cytotoxicity induced by ER stressors as well as the synergy between proteasome inhibitors and UPR-activators remained unaffected in BR cells. Based on our data, proteasome inhibitors with activity profiles different from that of Bortezomib, alone or in combination with induction of the UPR, may represent an appropriate concept to overcome secondary Bortezomib resistance.

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