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

[tetano]

Cell Rep


. 2022 Jul 4;111117.
doi: 10.1016/j.celrep.2022.111117. Online ahead of print.
Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition


Ju-Ri Sim ¹ , Dong Hoon Shin ¹ , Pil-Gu Park ² , So-Hyeon Park ³ , Joon-Yong Bae ⁴ , Youngchae Lee ¹ , Dha-Yei Kang ¹ , Ye Jin Kim ¹ , Sowon Aum ¹ , Shin Hye Noh ⁵ , Su Jin Hwang ² , Hye-Ran Cha ² , Cheong Bi Kim ² , Si Hwan Ko ² , Sunghoon Park ² , Dongkyu Jeon ³ , Sungwoo Cho ³ , Gee Eun Lee ⁴ , Jeonghun Kim ⁴ , Young-Hye Moon ⁶ , Jae-Ouk Kim ⁶ , Jae-Sung Nam ⁷ , Chang-Hoon Kim ⁷ , Sungmin Moon ⁸ , Youn Wook Chung ⁸ , Man-Seong Park ⁴ , Ji-Hwan Ryu ⁹ , Wan Namkung ¹⁰ , Jae Myun Lee ¹¹ , Min Goo Lee ¹²



Affiliations

• PMID: 35839776
• PMCID: PMC9250890
• DOI: 10.1016/j.celrep.2022.111117

Free PMC article

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 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).

Keywords: ANO6/TMEM16F; CP: Microbiology; SARS-CoV-2; phosphatidylserine; virus-cell fusion.