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

Abstract

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.

Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor

“…Therefore, it may be interesting to perform a clinical trial of SA4503 in SARS-CoV-2-infected patients. In addition, there are some additional sigma-1 receptor agonists for COVID-19 [ 74 ].…”

“…The two articles published in Nature and Science strongly suggest that the ER chaperone protein sigma-1 receptor plays an important role in the replication of SARS-CoV-2 in cells, and that the sigma-1 receptor is a promising therapeutic target for COVID-19 infection [ 41 , 42 , 44 , 74 , 88 ]. However, which pharmacological activity (i.e., agonist or antagonist) of sigma-1 receptor ligands is responsible for the blockade of SARS-CoV-2 replication remains uncertain.…”

Inhibition of SARS-CoV-2 infection in human cardiomyocytes by targeting the Sigma-1 receptor disrupts cytoskeleton architecture and contractility

“…Since S1R is engaged in ER protein synthesis and acts as chaperone for proteins translocating to cell surface (Vela, 2020), we investigated whether S1R inhibition could be related to modifications of the host cell receptor for viral entry. To that end, the expression of ACE2 was evaluated after a 24 h treatment with 1 μM of S1R antagonist NE-100.…”

“…Several compounds with antiviral activity have been proposed against SARS-CoV-2 infection, especially from drug repurposing studies (Lovato et al, 2020; Reznikov et al, 2020; Vela, 2020). Negative modulators of the Sigma-1 receptor (S1R) gained considerable attention in SARS-CoV-2 infection because of its interaction with non-structural protein 6 (NSP6) from SARS-CoV-2 (Gordon et al, 2020).…”

“…S1R binds ligands with very diverse structures from a wide spectrum of compounds and small molecules (Su et al, 2010; Tesei et al, 2018). Experimental and approved drugs that bind Sigma receptors with mild to high affinity, even as an off-target, have been considered to prevent or treat COVID-19 (Reznikov et al, 2020; Vela, 2020). Several of these compounds that inhibit S1R function have antiviral activity, including against other coronaviruses, but cardiotoxicity and induction of arrhythmias were also reported (Chen et al, 2006; Page et al, 2016).…”