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

Abstract

(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.

Accurate Prediction of Virus-Host Protein-Protein Interactions via a Siamese Neural Network Using Deep Protein Sequence Embeddings

“…Interactions predicted by our proposed model between JCV major capsid protein VP1 and receptors in brain cells showed a strong enrichment of different neurotransmitters, including serotonin receptors, which is in line with the current literature. For the SARS-Cov-2 spike protein, our model interestingly predicted for all virus variants an interaction with the sigma intracellular receptor 2, which might explain the cytopathic effects of sigma receptor binding ligands reported in the literature (Abate et al 2020, Gordon et al 2020, Ostrov et al 2021). In both cases recent techniques coming from the field of Explainable AI (XAI) allowed us to interpret model predictions and identify those parts of protein sequences, which according to our model mostly influence the prediction of respective protein-protein interactions.…”

“…In addition, sigma receptors have been proposed to be involved in the neuronal transmission of SARS-CoV-2 (Yesilkaya et al 2020). They have been suggested as a target for therapeutic intervention (Abate et al 2020, Gordon et al 2020, Ostrov et al 2021). Our results suggest that the observed antiviral effect observed in cell lines treated with sigma receptor binding ligands might be due to a modulated binding of the spike protein, hence inhibiting virus entry into cells.…”

Antibacterial properties of lactoferrin: A bibliometric analysis from 2000 to early 2022

“…Due to the SARS-CoV-2 outbreak leading the COVID-19 pandemic, the NP of this field after 2019 reached the highest level, which was verified by cluster 0 in Figures 4B , 5A , 6A . As a multifunctional protein with a broad-spectrum of antimicrobial activities, the molecular docking screening results indicate that LF can be used as a potential drug for the treatment of COVID-19 and also confirmed that a reasonable dose of LF exhibits anti-viral properties in SARS-CoV-2-infected cells ; LF combined with diphenhydramine can reduce the replication of the SARS-CoV-2 by 99% and can also shorten the recovery time of the new crown infection (Mirabelli et al, 2021 ; Ostrov et al, 2021 ). LF inhibits SARS-CoV-2 infection in cell models with multiple modes of action, including blocking viral attachment to cellular heparan sulfate and enhancing interferon responses (Hu et al, 2021 ).…”

Outcomes of 2111 COVID-19 Hospitalized Patients Treated with Hydroxychloroquine/Azithromycin and Other Regimens in Marseille, France, 2020: A Monocentric Retrospective Analysis

“… 19 Furthermore, specific agonists of the sigma-1 receptor showed an anti-viral effect but antagonists of this receptor did not. 18 Taken together, these results suggest that the antiviral effect of chloroquine on SARS-CoV-2 relies on several mechanisms but at least in part on agonist binding to sigma receptors, which is responsible for endoplasmic reticulum resistance to virus.…”

“… 16 , 17 In addition, coronaviruses, including SARS-CoV-2, activate and utilize endoplasmic reticulum stress and replicate in a modified endoplasmic reticulum-derived compartment. 18 Recent interactomics studies identified that chloroquine interferes with two non-structural viral protein-host protein interactions: nsp6 and the sigma-1 receptor, and Orf9c and the sigma-2 receptor. 14 , 15 Strikingly, both these sigma receptors are known to act as endoplasmic reticulum stress “gatekeepers”.…”