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

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 ANO...

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Autores principales: Sim, Ju-Ri, Shin, Dong Hoon, Park, Pil-Gu, Park, So-Hyeon, Bae, Joon-Yong, Lee, Youngchae, Kang, Dha-Yei, Kim, Ye Jin, Aum, Sowon, Noh, Shin Hye, Hwang, Su Jin, Cha, Hye-Ran, Kim, Cheong Bi, Ko, Si Hwan, Park, Sunghoon, Jeon, Dongkyu, Cho, Sungwoo, Lee, Gee Eun, Kim, Jeonghun, Moon, Young-hye, Kim, Jae-Ouk, Nam, Jae-Sung, Kim, Chang-Hoon, Moon, Sungmin, Chung, Youn Wook, Park, Man-Seong, Ryu, Ji-Hwan, Namkung, Wan, Lee, Jae Myun, Lee, Min Goo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Author(s). 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250890/
https://www.ncbi.nlm.nih.gov/pubmed/35839776
http://dx.doi.org/10.1016/j.celrep.2022.111117
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author Sim, Ju-Ri
Shin, Dong Hoon
Park, Pil-Gu
Park, So-Hyeon
Bae, Joon-Yong
Lee, Youngchae
Kang, Dha-Yei
Kim, Ye Jin
Aum, Sowon
Noh, Shin Hye
Hwang, Su Jin
Cha, Hye-Ran
Kim, Cheong Bi
Ko, Si Hwan
Park, Sunghoon
Jeon, Dongkyu
Cho, Sungwoo
Lee, Gee Eun
Kim, Jeonghun
Moon, Young-hye
Kim, Jae-Ouk
Nam, Jae-Sung
Kim, Chang-Hoon
Moon, Sungmin
Chung, Youn Wook
Park, Man-Seong
Ryu, Ji-Hwan
Namkung, Wan
Lee, Jae Myun
Lee, Min Goo
author_facet Sim, Ju-Ri
Shin, Dong Hoon
Park, Pil-Gu
Park, So-Hyeon
Bae, Joon-Yong
Lee, Youngchae
Kang, Dha-Yei
Kim, Ye Jin
Aum, Sowon
Noh, Shin Hye
Hwang, Su Jin
Cha, Hye-Ran
Kim, Cheong Bi
Ko, Si Hwan
Park, Sunghoon
Jeon, Dongkyu
Cho, Sungwoo
Lee, Gee Eun
Kim, Jeonghun
Moon, Young-hye
Kim, Jae-Ouk
Nam, Jae-Sung
Kim, Chang-Hoon
Moon, Sungmin
Chung, Youn Wook
Park, Man-Seong
Ryu, Ji-Hwan
Namkung, Wan
Lee, Jae Myun
Lee, Min Goo
author_sort Sim, Ju-Ri
collection PubMed
description 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 Ca(2+) 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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spelling pubmed-92508902022-07-05 Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition Sim, Ju-Ri Shin, Dong Hoon Park, Pil-Gu Park, So-Hyeon Bae, Joon-Yong Lee, Youngchae Kang, Dha-Yei Kim, Ye Jin Aum, Sowon Noh, Shin Hye Hwang, Su Jin Cha, Hye-Ran Kim, Cheong Bi Ko, Si Hwan Park, Sunghoon Jeon, Dongkyu Cho, Sungwoo Lee, Gee Eun Kim, Jeonghun Moon, Young-hye Kim, Jae-Ouk Nam, Jae-Sung Kim, Chang-Hoon Moon, Sungmin Chung, Youn Wook Park, Man-Seong Ryu, Ji-Hwan Namkung, Wan Lee, Jae Myun Lee, Min Goo Cell Rep Article 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 Ca(2+) 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). The Author(s). 2022-07-19 2022-07-04 /pmc/articles/PMC9250890/ /pubmed/35839776 http://dx.doi.org/10.1016/j.celrep.2022.111117 Text en © 2022 The Author(s) Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Sim, Ju-Ri
Shin, Dong Hoon
Park, Pil-Gu
Park, So-Hyeon
Bae, Joon-Yong
Lee, Youngchae
Kang, Dha-Yei
Kim, Ye Jin
Aum, Sowon
Noh, Shin Hye
Hwang, Su Jin
Cha, Hye-Ran
Kim, Cheong Bi
Ko, Si Hwan
Park, Sunghoon
Jeon, Dongkyu
Cho, Sungwoo
Lee, Gee Eun
Kim, Jeonghun
Moon, Young-hye
Kim, Jae-Ouk
Nam, Jae-Sung
Kim, Chang-Hoon
Moon, Sungmin
Chung, Youn Wook
Park, Man-Seong
Ryu, Ji-Hwan
Namkung, Wan
Lee, Jae Myun
Lee, Min Goo
Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition
title Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition
title_full Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition
title_fullStr Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition
title_full_unstemmed Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition
title_short Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition
title_sort amelioration of sars-cov-2 infection by ano6 phospholipid scramblase inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250890/
https://www.ncbi.nlm.nih.gov/pubmed/35839776
http://dx.doi.org/10.1016/j.celrep.2022.111117
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