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

David A Ostrov,Christopher R Mccurdy,Karthic Rajamanickam,Danmeng Li,Joyce A Wilson,Darryl Falzarano,Megha Rohamare,Siva Rama Raju Kanumuri,Abhisheak Sharma,Andrew P Bluhm,Michael H Norris,Jocelyne Lew,Juveriya Qamar Khan,Kalpana K Bhanumathy,Franco J Vizeacoumar,Marco Mottinelli

doi:10.3390/pathogens10111514

David A Ostrov, Christopher R Mccurdy + Show 14 more

Open Access

https://doi.org/10.3390/pathogens10111514

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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.

Highlights

There is a strong need for safe drugs and vaccines to target emerging pathogens such as SARS-CoV-2
Indicated non- target sigma receptors had potential for0.1 further analysis
Ligands that and non- target sigma receptors had potential furWith ligand concentrations used in these preliminary studies as a starting point, for toxicity ther analysis

Summary

Introduction

There is a strong need for safe drugs and vaccines to target emerging pathogens such as SARS-CoV-2. Recent studies identified approved drugs that exhibit antiviral activities against SARS-CoV-2 [1,2], current therapeutic treatment strategies for COVID-19 have limited effectiveness. There are currently no oral medications given emergency use authorization from the Food and Drug Administration to prevent SARSCoV-2 infection or to treat COVID-19. There is an urgent need to identify safe, economical, orally deliverable approved drugs with activity against SARS-CoV-2 to prevent infection in at-risk populations, and to treat patients experiencing viral disease [3]. Attempts to identify approved drugs with antiviral activity led to the discovery of more than 100 compounds that exhibit direct antiviral activity against SARS-CoV-2 isolates in vitro [2,4,5,6]. The on- and off-target binding mechanisms that mediate anti-SARS-CoV-2 activity are not clear, two classes of molecules were previously found to effectively inhibit virus infectivity: protein biogenesis inhibitors (e.g., zotatifin, ternatin-4, PS3061) and ligands of the sigma-1 and sigma-2 receptors (e.g., haloperidol, clemastine, cloperastine) [7]

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