Front Pharmacol. 2020 Nov 9;11:582310. doi: 10.3389/fphar.2020.582310. eCollection 2020.
Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?
José Miguel Vela 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.
Front Pharmacol. 2020 Dec 7;11:589810. doi: 10.3389/fphar.2020.589810. eCollection 2020.
PB28, the Sigma-1 and Sigma-2 Receptors Modulator With Potent Anti-SARS-CoV-2 Activity: A Review About Its Pharmacological Properties and Structure Affinity Relationships
Carmen Abate 1, Mauro Niso 1, Francesca Serena Abatematteo 1, Marialessandra Contino 1, Nicola Antonio Colabufo 1, Francesco Berardi 1
These unprecedented times have forced the scientific community to gather to face the COVID-19 pandemic. Efforts in diverse directions have been made. A multi-university team has focused on the identification of the host (human) proteins interacting with SARS-CoV-2 viral proteins, with the aim of hampering these interactions that may cause severe COVID-19 symptoms. Sigma-1 and sigma-2 receptors surprisingly belong to the “druggable” host proteins found, with the pan-sigma receptor modulator PB28 displaying the most potent anti-SARS-CoV-2 activity in in vitro assays. Being 20-fold more active than hydroxychloroquine, without cardiac side effects, PB28 is a promising antiviral candidate worthy of further investigation. Our research group developed PB28 in 1996 and have thoroughly characterized its biological properties since then. Structure-affinity relationship (SAfiR) studies at the sigma receptor subtypes were also undertaken with PB28 as the lead compound. We herein report our knowledge of PB28 to share information that may help to gain insight into the antiviral action of this compound and sigma receptors, while providing structural hints that may speed up the translation into therapeutics of this class of ligands.
J Clin Neurosci. 2020 Oct; 80: 72–73.
Reissuing the sigma receptors for SARS-CoV-2
Umit Haluk Yesilkaya, Yasin Hasan Balcioglu,⁎ and Serhat Sahin
- Receptor binding is a major determinant of tissue tropism for SARS-CoV-2.
- Neurotropism of SARS-CoV-2 associated with a broad range of receptors in the central nervous system (CNS).
- Sigma receptors may be involved in the neuronal transmission of SARS-CoV-2.
Receptor binding is one of the major determinants of tissue tropism for coronaviruses and seems an important mediator of the pathophysiology of COVID-19. With this regard, the emerging review article published in the Journal by Armocida et al. has drawn our special attention to the possible involvement of a broad range of receptors in the neurotropism and neuronal cell entry of SARS-CoV-2 . Despite the effects of SARS-CoV-2 on the central nervous system (CNS) currently remained inconclusive, a foregoing line of evidence supports the hermeneutical notion that the CNS transmission of SARS-CoV-2 might be via either direct viral infiltration or angiotensin-converting enzyme-2 receptors , . Alternatively and presumably, the recent interactome study by Gordon et al. adumbrated that Sigma1 (σ1) and Sigma2 (σ2) receptors might play a role in the neuronal infectivity of SARS-CoV-2  .
Both σ1 and σ2 are widely expressed in the CNS structures including the spinal cord, pons, cerebellum, hippocampus, hypothalamus, midbrain, cerebral cortex and olfactory bulb. Protein architecture of σ1 incorporates cholesterol-binding chaperones that are located in lipid-rich regions of the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs). These ER-embedded protein microdomains have been attributed to maintaining Ca+2 signals and involving in lipid storage and transport in MAMs. These functions of σ1 have also been postulated to take part in the mediation of the early stages of viral RNA replication. Previous research has suggested that pharmacological manipulation of both σ1 and σ2 activity might provide antiviral activity, particularly for RNA viruses including hepatitis C virus (HCV) and human immunodeficiency viruses (HIV). Functional deficiency and reduced expression of σ1 might be associated with decreased intracellular titration of HCV-RNA , while a pharmacological selective σ1 antagonist BD1047 has been shown to alter the stimulating effect of cocaine on the intracellular HIV-1 expression in microglia . These findings indicate that σ receptors may also be involved in the neuronal transmission of SARS-CoV-2, which has a genome structure similar to those of HCV and HIV. Clinical observations that many patients with COVID-19 present with anosmia may empirically support our argument as SARS-CoV-2 might have an affinity to olfactor bulb which is enriched in σ receptors. Another important implication of σ receptor involvement in the SARS-CoV-2 infection may lie in the argument that numerous psychotropics likes of haloperidol, fluvoxamine, fluphenazine and chlorpromazine considerably interacts with σ receptors, which may highlight the potential clinical utility of such agents in the management of SARS-CoV-2 infection. Nevertheless, such an argument needs decent support from well-established clinical research. Although abovementioned postulations galvanize our interest in the comprehension of the pathophysiology of CNS involvement of SARS-CoV-2, we disclose that much more work is required to illuminate and guide the specific underpinnings of SARS-CoV-2’s brain involvement.
ACS Med Chem Lett. 2020 Oct 8; 11(10): 2048–2050.
Why PB28 Could Be a Covid 2019 Game Changer?
Nicola Antonio Colabufo,corresponding author* Marcello Leopoldo, Savina Ferorelli, Carmen Abate, Marialessandra Contino, Maria Grazia Perrone, Mauro Niso, Roberto Perrone, and Francesco Berardi
PB28, a cyclohexylpiperazine derivative, could be a potential strategy for Covid 19 because in a recent study it has been found more active than hydroxychloroquine without interaction with cardiac proteins. PB28 has been designed, developed, and biologically evaluated in the past decade in our research group. A possible mechanism to explain its surprising anti-COVID-19 activity is suggested..
Nature volume 583, pages459–468(2020)Cite this article. Published: 30 April 2020
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
David E. Gordon, Gwendolyn M. Jang, […]Nevan J. Krogan
A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.