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Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibitionopen access

Authors
Sim, Ju-RiShin, Dong HoonPark, Pil-GuPark, So-HyeonBae, Joon-YongLee, YoungchaeKang, Dha-YeiKim, Ye JinAum, SowonNoh, Shin HyeHwang, Su JinCha, Hye-RanKim, Cheong BiKo, Si HwanPark, SunghoonJeon, DongkyuCho, SungwooLee, Gee EunKim, JeonghunMoon, Young-hyeKim, Jae-OukNam, Jae-SungKim, Chang-HoonMoon, SungminChung, Youn WookPark, Man-SeongRyu, Ji-HwanNamkung, WanLee, Jae MyunLee, Min Goo
Issue Date
19-7월-2022
Publisher
CELL PRESS
Keywords
ANO6/TMEM16F; CP: Microbiology; phosphatidylserine; SARS-CoV-2; virus-cell fusion
Citation
CELL REPORTS, v.40, no.3
Indexed
SCIE
SCOPUS
Journal Title
CELL REPORTS
Volume
40
Number
3
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/146621
DOI
10.1016/j.celrep.2022.111117
ISSN
2211-1247
Abstract
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 Ca2+ elevation and ANO6-dependent phosphatidylserine externalization in ACE2/TMPRSS2-positive mammalian cells. A high-throughput screening of drug-like chemical libraries iden-tifies three different structural classes of chemicals showing ANO6 inhibitory effects. Among them, A6-001 dis-plays 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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