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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 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 
 CELL REPORTS, Vol.40(3) : 111117, 2022-07 
Journal Title
Issue Date
Angiotensin-Converting Enzyme 2 ; Animals ; Anoctamins ; COVID-19* / drug therapy ; Humans ; Mammals / metabolism ; Phosphatidylserines ; Phospholipid Transfer Proteins / metabolism ; SARS-CoV-2 ; Virus Internalization
ANO6/TMEM16F ; CP: Microbiology ; SARS-CoV-2 ; phosphatidylserine ; virus-cell fusion
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).
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Chang Hoon(김창훈) ORCID logo https://orcid.org/0000-0003-1238-6396
Nam, Jae Sung(남재성) ORCID logo https://orcid.org/0000-0002-3428-8108
Noh, Shin Hye(노신혜) ORCID logo https://orcid.org/0000-0003-3118-9240
Shin, Dong Hoon(신동훈)
Ryu, Ji Hwan(유지환)
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
Lee, Youngchae(이영채) ORCID logo https://orcid.org/0000-0002-5015-429X
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
Chung, Youn Wook(정연욱) ORCID logo https://orcid.org/0000-0002-4382-1410
Cha, Hye-Ran(차혜란)
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