期刊
PATHOGENS
卷 10, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/pathogens10111514
关键词
drug discovery; sigma-1 receptor; SARS-CoV-2; molecular docking; antiviral therapeutics
类别
资金
- Emerging Pathogens Institute start-up funds
- University of Florida Clinical and Translational Science Institute
- NIH National Center for Advancing Translational Sciences [UL1TR001427]
- Canadian Institutes of Health Research (CIHR) Institute of Infection and Immunity [VR3-172626]
The study identified sigma receptor ligands with agonism of the sigma-1 receptor, ligation of the sigma-2 receptor, and a combination of the two pathways as effective in inhibiting SARS-CoV-2 infection, offering a potential therapeutic avenue for COVID-19 prevention and treatment in primate and human cells.
(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.
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