Significance The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the etiological agent of coronavirus disease-2019 (COVID-19), has swept the world in unprecedented speed. In a few months, SARS-CoV-2 has infected millions of people and caused tens of thousands of deaths. There are no Food and Drug Administration-approved antivirals or vaccines yet available and clinical treatments are limited to supportive therapies that help alleviate the symptoms. Thus, there is an urgent need to identify effective antivirals as countermeasures before safe and effective vaccines are developed, tested, and then produced on a large scale. Our approach is to harness the germline-encoded interferon antiviral response to inhibit SARS-CoV-2 replication thereby limiting its pathogenicity. Cholesterol 25-hydroxylase ( CH25H ) is an interferon (IFN)-stimulated gene that shows broad antiviral activities against a wide range of enveloped viruses. Here, using an IFN-stimulated gene screen against vesicular stomatitis virus (VSV)-SARS-CoV and VSV-SARS-CoV-2 chimeric viruses, we identified CH25H and its enzymatic product 25-hydroxycholesterol (25HC) as potent inhibitors of SARS-CoV-2 replication. Internalized 25HC accumulates in the late endosomes and potentially restricts SARS-CoV-2 spike protein catalyzed membrane fusion via blockade of cholesterol export. Our results highlight one of the possible antiviral mechanisms of 25HC and provide the molecular basis for its therapeutic development.
【저자키워드】 COVID-19, SARS-CoV-2, Innate immunity, interferon, virus entry, 【초록키워드】 coronavirus disease, viruses, Vaccine, coronavirus, Antiviral, interferon, drug, antiviral activity, Symptoms, Spike protein, coronavirus disease-2019, Replication, SARS-CoV-2 spike protein, therapeutic, membrane fusion, cholesterol, respiratory, pathogenicity, SARS-CoV-2 replication, mechanism, vesicular stomatitis virus, Coronavirus-2, food, antiviral response, Clinical treatment, deaths, Safe, chimeric, antiviral activities, vesicular stomatitis, supportive therapies, supportive therapy, acute respiratory syndrome, acute respiratory syndrome coronavirus, inhibitors of SARS-CoV-2, acute respiratory syndrome coronavirus-2, help, Effective vaccines, Drug administration, germline, molecular basis, blockade, etiological agent, stomatitis, CH25H, late endosomes, approach, effective, highlight, produced, tested, identify, caused, restrict, effective vaccine, accumulate, catalyzed, alleviate, inhibit SARS-CoV-2, late endosome, Significance, 【제목키워드】 membrane fusion, cholesterol, suppresse,