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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 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). Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.


Ju-Ri Sim, Dong Hoon Shin, Pil-Gu Park, So-Hyeon Park, Joon-Yong Bae, Youngchae Lee, Dha-Yei Kang, Ye Jin Kim, Sowon Aum, Shin Hye Noh, Su Jin Hwang, Hye-Ran Cha, Cheong Bi Kim, Si Hwan Ko, Sunghoon Park, Dongkyu Jeon, Sungwoo Cho, Gee Eun Lee, Jeonghun Kim, Young-Hye Moon, Jae-Ouk Kim, Jae-Sung Nam, Chang-Hoon Kim, Sungmin Moon, Youn Wook Chung, Man-Seong Park, Ji-Hwan Ryu, Wan Namkung, Jae Myun Lee, Min Goo Lee. Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition. Cell reports. 2022 Jul 19;40(3):111117

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PMID: 35839776

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