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Highly Specific Sigma Receptor Ligands Exhibit Anti-Viral Properties in SARS-CoV-2 Infected Cells
David A Ostrov1, Andrew P Bluhm2,3, Danmeng Li1
1Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Pathogens (Basel, Switzerland)
|November 27, 2021
Summary
New research shows that targeting host sigma receptors with specific ligands can inhibit SARS-CoV-2 replication and cellular toxicity. These findings offer a promising therapeutic strategy for COVID-19 prevention and treatment, unaffected by viral mutations.
Area of Science:
- Virology
- Pharmacology
- Cell Biology
Background:
- Emerging SARS-CoV-2 variants necessitate novel COVID-19 prevention and treatment strategies.
- Host ER resident sigma receptors interact with SARS-CoV-2 proteins in the replication complex.
Purpose of the Study:
- To investigate the potential of sigma receptor ligands in inhibiting SARS-CoV-2 replication and associated cellular toxicity.
- To explore novel therapeutic avenues for COVID-19 treatment.
Main Methods:
- Utilized highly specific sigma receptor ligands (agonists and antagonists) to target sigma-1 and sigma-2 receptors.
- Assessed inhibition of SARS-CoV-2 genome replication and virus-induced cellular toxicity.
- Employed structural modeling to identify intermolecular contacts between ligands and sigma receptors.
Main Results:
- Identified antiviral activity with sigma-1 receptor agonism (e.g., SA4503) and sigma-2 receptor ligation (e.g., CM398).
- Demonstrated synergistic antiviral effects with combined sigma receptor pathway modulation (e.g., AZ66).
- Structural modeling elucidated ligand-receptor interactions.
Conclusions:
- Sigma receptor ligands effectively inhibit SARS-CoV-2 infection in primate and human cells.
- Drugs with off-target sigma receptor binding also show efficacy.
- These findings represent a potential therapeutic avenue for COVID-19 prevention and treatment, independent of viral mutations.
