Highly Specific Sigma Receptor Ligands Exhibit Anti-viral Properties in SARS-CoV-2 Infected Cells

(1) Background: There is a strong need for prevention and treatment strategies for COVID-19 that are not impacted by SARS-CoV-2 mutations emerging in variants of concern. After virus infection, host ER resident sigma receptors form direct interactions with non-structural SARS-CoV-2 proteins present in the replication complex. (2) Methods: In this work, highly specific sigma receptor ligands were investigated for their ability to inhibit both SARS-CoV-2 genome replication and virus induced cellular toxicity. This study found antiviral activity associated with agonism of the sigma-1 receptor (e.g., SA4503), ligation of the sigma-2 receptor (e.g., CM398), and a combination of the two pathways (e.g., AZ66). (3) Results: Intermolecular contacts between these ligands and sigma receptors were identified by structural modeling. (4) Conclusions: Sigma receptor ligands and drugs with off-target sigma receptor binding characteristics were effective at inhibiting SARS-CoV-2 infection in primate and human cells, representing a potential therapeutic avenue for COVID-19 prevention and treatment.

Multifunctional thiosemicarbazones targeting sigma receptors: in vitro and in vivo antitumor activities in pancreatic cancer models

Purpose Association of the metal chelating portion of thiosemicarbazone with the cytotoxic activity of sigma-2 receptors appears a promising strategy for the treatment of pancreatic tumors. Here, we developed a novel sigma-2 receptor targeting thiosemicarbazone (FA4) that incorporates a moiety associated with lysosome destabilization and ROS increase in order to design more efficient antitumor agents. Methods The density of sigma receptors in pancreatic cancer cells was evaluated by flow cytometry. In these cells, cytotoxicity (MTT assay) and activation of ER- and mitochondria-dependent cell death pathways (mRNA expression of GRP78, ATF6, IRE1, PERK; ROS levels by MitoSOX and DCFDA-AM; JC-1 staining) induced by the thiosemicarbazones FA4, MLP44, PS3 and ACthio-1, were evaluated. The expression of autophagic proteins (ATG5, ATG7, ATG12, beclin, p62 and LC3-I) was also studied. In addition, the in vivo effect of FA4 in xenograft models with and without gemcitabine challenge was investigated. Results We found that FA4 exerted a more potent cytotoxicity than previously studied thiosemicarbazones (MLP44, PS3 and ACthio-1), which were found to display variable effects on the ER or the mitochondria-dependent pro-apoptotic axis. By contrast, FA4 activated pro-apoptotic pathways and decreased autophagy, except in MiaPaCa2 cells, in which autophagic proteins were expressed at lower levels and remained unmodified by FA4. FA4 treatment of PANC-1 xenografted mouse models, poorly responsive to conventional chemotherapy, significantly reduced tumor volumes and increased intratumor apoptosis compared to gemcitabine, with no signs of toxicity. Conclusions Our data indicate that FA4 exhibits encouraging activity in pancreatic cancer cells unresponsive to gemcitabine. These results warrant further investigation in patient-derived pancreatic cancers, and hold promise for the development of therapies that can more efficiently target the specific characteristics of individual tumor types.

Sigma receptors and neurological disorders

AbstarctSigma receptors were identified relatively recently, and their presence has been confirmed in the central nervous system and peripheral organs. Changes in sigma receptor function or expression may be involved in neurological diseases, and thus sigma receptors represent a potential target for treating central nervous system disorders. Many substances that are ligands for sigma receptors are widely used in therapies for neurological disorders. In the present review, we discuss the roles of sigma receptors, especially in the central nervous system disorders, and related therapies. Graphic abstract

Design, Synthesis, and Evaluation of Novel, Selective γ-butyrolactones Sigma-2 Ligands

Nearly 40 years after the first disclosure of sigma receptors, the sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein). This macromolecule has been associated with a number of disease states such as schizophrenia, Alzheimer’s disease, neuropathic pain, traumatic brain injury, and cancer. We have recently identified a series of novel, functionalized γ-butyrolactones that are potent σ2 receptor ligands that are drug-like and identified a potential candidate (9z) for future in vivo study.

Combination of Heme Oxygenase-1 Inhibition and Sigma Receptor Modulation for Anticancer Activity

Cancer is a multifactorial disease that may be tackled by targeting different signaling pathways. Heme oxygenase-1 (HO-1) and sigma receptors (Rs) are both overexpressed in different human cancers, including prostate and brain, contributing to the cancer spreading. In the present study, we investigated whether HO-1 inhibitors and R ligands, as well a combination of the two, may influence DU145 human prostate and U87MG human glioblastoma cancer cells proliferation. In addition, we synthesized, characterized, and tested a small series of novel hybrid compounds (HO-1/Rs) 14 containing the chemical features needed for HO-1 inhibition and R modulation. Herein, we report for the first time that targeting simultaneously HO-1 and R proteins may be a good strategy to achieve increased antiproliferative activity against DU145 and U87MG cells, with respect to the mono administration of the parent compounds. The obtained outcomes provide an initial proof of concept useful to further optimize the structure of HO-1/Rs hybrids to develop novel potential anticancer agents.

O26: SIGMA RECEPTORS IN BREAST CANCER – EXAMINING THEIR LIGAND MEDIATED MECHANISMS OF CANCER CELL DEATH AND POTENTIAL FOR CLINICAL DIAGNOSTICS

Introduction Sigma receptors (SRs) are regularly overexpressed in cancer however their functions remain unknown. Certain Sigma1-receptor (Sig1R) ligands trigger death in breast cancer (BCa) cells but not in non-cancerous breast cells (NCB). In stressed cells, Sig1R is vital to the pro-survival unfolded protein response (UPR). Cancer cells depend on UPR signalling for survival, investigating Sig1R mediated mechanisms in BCa vs. NCB might uncover novel and targetable weaknesses in cancer. Method UPR activation by Sig1R antagonist IPAG was examined in BCa cells by Western blotting. Sig1R and UPR marker localizations were examined by immunofluorescence. SR gene expression between 141 matched breast tumour tissue and tumour adjacent normal samples was compared using RNAseq data from The Cancer Genome Atlas (TCGA). Merged microarray datasets were used to compare SR expression in 399 primary breast tumours with relapse (BCaR) vs. 352 without relapse (BCaNR). Result Relative to non-cancerous human mammary epithelial cells, Sig1R expression was lowest in MCF7s and highest in MDA-MB-468s. IPAG induced differential temporal activation of all three branches of the UPR in MCF7 and tamoxifen-resistant, low Sig1R expressing cell line LY2. TCGA RNAseq data highlighted SR overexpression in BCa particularly in the basal subtype. Microarray data showed both oestrogen receptor (ER)+ and ER- BCaR primaries had elevated SIGMAR1 compared to BCaNR primaries of the same respective ER status. Conclusion BCa cells are dependent on Sig1R mediated signalling. Sig1R expression might indicate the propensity of breast tumours to relapse. Thus, Sig1R represents a potential target in BCa, particularly for aggressive subtypes. Take-home message The Sigma-1 receptor (Sig1R) has a vital but unknown pro-survival function in cancer; Sig1R ligands cause death in cancer cells while sparing non-cancerous ones. Characterizing Sig1R mediated signalling may reveal novel, selective therapeutic targets in cancer.

Sigma-2 Receptor—A Potential Target for Cancer/Alzheimer’s Disease Treatment via Its Regulation of Cholesterol Homeostasis

The sigma receptors were classified into sigma-1 and sigma-2 receptor based on their different pharmacological profiles. In the past two decades, our understanding of the biological and pharmacological properties of the sigma-1 receptor is increasing; however, little is known about the sigma-2 receptor. Recently, the molecular identity of the sigma-2 receptor has been identified as TMEM97. Although more and more evidence has showed that sigma-2 ligands have the ability to treat cancer and Alzheimer’s disease (AD), the mechanisms connecting these two diseases are unknown. Data obtained over the past few years from human and animal models indicate that cholesterol homeostasis is altered in AD and cancer, underscoring the importance of cholesterol homeostasis in AD and cancer. In this review, based on accumulated evidence, we proposed that the beneficial roles of sigma-2 ligands in cancer and AD might be mediated by their regulation of cholesterol homeostasis.