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

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 MoonJae 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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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).

Original languageEnglish
Article number111117
JournalCell Reports
Volume40
Issue number3
DOIs
Publication statusPublished - 2022 Jul 19

Keywords

  • ANO6/TMEM16F
  • CP: Microbiology
  • SARS-CoV-2
  • phosphatidylserine
  • virus-cell fusion

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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