Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition.

Cell Rep

Department of Pharmacology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea; Severance Biomedical Science Institute, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea. Electronic address:

Published: July 2022

As an enveloped virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) delivers its viral genome into host cells via fusion of the viral and cell membranes. Here, we show that ANO6/TMEM16F-mediated cell surface exposure of phosphatidylserine is critical for SARS-CoV-2 entry and that ANO6-selective inhibitors are effective against SARS-CoV-2 infections. Application of the SARS-CoV-2 Spike pseudotyped virus (SARS2-PsV) evokes a cytosolic Ca elevation and ANO6-dependent phosphatidylserine externalization in ACE2/TMPRSS2-positive mammalian cells. A high-throughput screening of drug-like chemical libraries identifies three different structural classes of chemicals showing ANO6 inhibitory effects. Among them, A6-001 displays the highest potency and ANO6 selectivity and it inhibits the single-round infection of SARS2-PsV in ACE2/TMPRSS2-positive HEK 293T cells. More importantly, A6-001 strongly inhibits authentic SARS-CoV-2-induced phosphatidylserine scrambling and SARS-CoV-2 viral replications in Vero, Calu-3, and primarily cultured human nasal epithelial cells. These results provide mechanistic insights into the viral entry process and offer a potential target for pharmacological intervention to protect against coronavirus disease 2019 (COVID-19).

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250890PMC
http://dx.doi.org/10.1016/j.celrep.2022.111117DOI Listing

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