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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Published in | Cell reports (Cambridge) Vol. 40; no. 3; p. 111117 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
19.07.2022
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Subjects | |
Online Access | Get full text |
ISSN | 2211-1247 2211-1247 |
DOI | 10.1016/j.celrep.2022.111117 |
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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).
[Display omitted]
•A high-throughput screening of chemical libraries identifies several ANO6 inhibitors•SARS-CoV-2 Spike evokes ANO6-mediated phosphatidylserine scrambling in host cells•Phosphatidylserine scrambling promotes fusion of the viral and cell membranes•The identified ANO6 inhibitors inhibit SARS-CoV-2 viral replications
Sim et al. show that ANO6/TMEM16F-mediated phosphatidylserine scrambling participates in the SARS-CoV-2 entry into host cells and ANO6 inhibitors are effective against SARS-CoV-2 infection. These findings provide mechanistic insights into the viral entry process as well as a potential target for the development of drugs to treat COVID-19. |
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AbstractList | 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).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). 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). [Display omitted] •A high-throughput screening of chemical libraries identifies several ANO6 inhibitors•SARS-CoV-2 Spike evokes ANO6-mediated phosphatidylserine scrambling in host cells•Phosphatidylserine scrambling promotes fusion of the viral and cell membranes•The identified ANO6 inhibitors inhibit SARS-CoV-2 viral replications Sim et al. show that ANO6/TMEM16F-mediated phosphatidylserine scrambling participates in the SARS-CoV-2 entry into host cells and ANO6 inhibitors are effective against SARS-CoV-2 infection. These findings provide mechanistic insights into the viral entry process as well as a potential target for the development of drugs to treat COVID-19. 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). Sim et al. show that ANO6/TMEM16F-mediated phosphatidylserine scrambling participates in the SARS-CoV-2 entry into host cells and ANO6 inhibitors are effective against SARS-CoV-2 infection. These findings provide mechanistic insights into the viral entry process as well as a potential target for the development of drugs to treat COVID-19. 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 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). |
ArticleNumber | 111117 |
Author | Bae, Joon-Yong Park, So-Hyeon Shin, Dong Hoon Cho, Sungwoo Kim, Chang-Hoon Moon, Young-hye Lee, Jae Myun Aum, Sowon Jeon, Dongkyu Kang, Dha-Yei Park, Pil-Gu Cha, Hye-Ran Sim, Ju-Ri Moon, Sungmin Hwang, Su Jin Chung, Youn Wook Kim, Ye Jin Kim, Cheong Bi Ryu, Ji-Hwan Lee, Gee Eun Namkung, Wan Lee, Youngchae Noh, Shin Hye Park, Man-Seong Ko, Si Hwan Kim, Jeonghun Kim, Jae-Ouk Lee, Min Goo Park, Sunghoon Nam, Jae-Sung |
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Lee, Min Goo email: mlee@yuhs.ac organization: Department of Pharmacology, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea |
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Keywords | phosphatidylserine SARS-CoV-2 CP: Microbiology ANO6/TMEM16F virus-cell fusion |
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Virol. doi: 10.1007/BF01718208 |
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Snippet | 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... |
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StartPage | 111117 |
SubjectTerms | Angiotensin-Converting Enzyme 2 Animals ANO6/TMEM16F Anoctamins COVID-19 Drug Treatment Humans Mammals - metabolism phosphatidylserine Phosphatidylserines Phospholipid Transfer Proteins - metabolism SARS-CoV-2 Virus Internalization virus-cell fusion |
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Title | Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition |
URI | https://dx.doi.org/10.1016/j.celrep.2022.111117 https://www.ncbi.nlm.nih.gov/pubmed/35839776 https://www.proquest.com/docview/2691049438 https://pubmed.ncbi.nlm.nih.gov/PMC9250890 |
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