SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae , displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.
【저자키워드】 Infection, Medical genomics, 【초록키워드】 COVID-19, Treatment, viruses, SARS-CoV-2, clinical trial, pandemic, Biomarker, severe COVID-19, spike, variant, clinical trials, variants, Spike protein, Antiviral effect, Protein, Viral, SARS-CoV-2 spike protein, target, Ebola, RNA virus, Mouse models, inhibitor, therapeutic strategy, compounds, Interaction, the cell, family members, infected patients, enzymatic activity, germline, E3 ligase, Cell, Brassicaceae, NEDD4, WWP1, responsible, identify, inhibit, implicated, overexpressed, activating, COVID-19 infected patient, the SARS-CoV-2, VP40, 【제목키워드】 COVID-19, inhibition, E3 ligase, potential therapy,