Inhibition of HECT E3 ligases as potential therapy for COVID-19.

TitleInhibition of HECT E3 ligases as potential therapy for COVID-19.
Publication TypeJournal Article
Year of Publication2021
AuthorsNovelli, G, Liu, J, Biancolella, M, Alonzi, T, Novelli, A, Patten, JJ, Cocciadiferro, D, Agolini, E, Colona, VLuigi, Rizzacasa, B, Giannini, R, Bigio, B, Goletti, D, Capobianchi, MRosaria, Grelli, S, Mann, J, McKee, TD, Cheng, K, Amanat, F, Krammer, F, Guarracino, A, Pepe, G, Tomino, C, Tandjaoui-Lambiotte, Y, Uzunhan, Y, Tubiana, S, Ghosn, J, Notarangelo, LD, Su, HC, Abel, L, Cobat, A, Elhanan, G, Grzymski, JJ, Latini, A, Sidhu, SS, Jain, S, Davey, RA, Casanova, J-L, Wei, W, Pandolfi, PPaolo
Corporate AuthorsCOVID Human Genetic Effort, French COVID Cohort Study Group, CoV-Contact Cohort
JournalCell Death Dis
Date Published2021 03 24
KeywordsAdult, Aged, Animals, Antiviral Agents, Chlorocebus aethiops, COVID-19, Endosomal Sorting Complexes Required for Transport, Female, Humans, Indoles, Male, Mice, Mice, Inbred BALB C, Middle Aged, Nedd4 Ubiquitin Protein Ligases, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Ubiquitin-Protein Ligases, Ubiquitination, Vero Cells

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.

Alternate JournalCell Death Dis
PubMed ID33762578
PubMed Central IDPMC7987752
Grant ListANR-10-IAHU-01 / / Agence Nationale de la Recherche (French National Research Agency) /
ANR-10-IAHU-01 / / Agence Nationale de la Recherche (French National Research Agency) /
ANR-10-LABX-62-IBEID / / Agence Nationale de la Recherche (French National Research Agency) /
/ HH / Howard Hughes Medical Institute / United States
R01 AI088364 / AI / NIAID NIH HHS / United States
UL1 TR001866 / TR / NCATS NIH HHS / United States
UM1 HG006504 / HG / NHGRI NIH HHS / United States
U24 HG008956 / HG / NHGRI NIH HHS / United States