(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.
【저자키워드】 SARS-CoV-2, Drug discovery, molecular docking, antiviral therapeutics, sigma-1 receptor, 【초록키워드】 COVID-19, Treatment, SARS-COV-2 infection, variants of concern, Toxicity, drug, antiviral activity, virus, Replication, Characteristics, SARS-CoV-2 genome, therapeutic, pathway, receptor, virus infection, SARS-CoV-2 mutation, cellular, Combination, Ligand, Interaction, Receptor binding, treatment strategy, Contact, complex, human cells, SARS-CoV-2 protein, sigma, Host, effective, investigated, inhibit, representing, inhibiting, impacted, SA4503, 【제목키워드】 property, sigma, Specific,