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

doi:10.1016/j.celrep.2022.111117

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 journal › Article › peer-review

16 Citations (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 language	English
Article number	111117
Journal	Cell Reports
Volume	40
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2022.111117
Publication status	Published - 2022 Jul 19

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Keywords

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

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2022.111117

Cite this

Sim, J. R., Shin, D. H., Park, P. G., Park, S. H., Bae, J. Y., Lee, Y., Kang, D. Y., Kim, Y. J., Aum, S., Noh, S. H., Hwang, S. J., Cha, H. R., Kim, C. B., Ko, S. H., Park, S., Jeon, D., Cho, S., Lee, G. E., Kim, J., ... Lee, M. G. (2022). Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition. Cell Reports, 40(3), Article 111117. https://doi.org/10.1016/j.celrep.2022.111117

Sim, JR, Shin, DH, Park, PG, Park, SH, Bae, JY, Lee, Y, Kang, DY, Kim, YJ, Aum, S, Noh, SH, Hwang, SJ, Cha, HR, Kim, CB, Ko, SH, Park, S, Jeon, D, Cho, S, Lee, GE, Kim, J, Moon, YH, Kim, JO, Nam, JS, Kim, CH, Moon, S, Chung, YW, Park, MS, Ryu, JH, Namkung, W, Lee, JM & Lee, MG 2022, 'Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition', Cell Reports, vol. 40, no. 3, 111117. https://doi.org/10.1016/j.celrep.2022.111117

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title = "Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition",

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).",

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author = "Sim, {Ju Ri} and Shin, {Dong Hoon} and Park, {Pil Gu} and Park, {So Hyeon} and Bae, {Joon Yong} and Youngchae Lee and Kang, {Dha Yei} and Kim, {Ye Jin} and Sowon Aum and Noh, {Shin Hye} and Hwang, {Su Jin} and Cha, {Hye Ran} and Kim, {Cheong Bi} and Ko, {Si Hwan} and Sunghoon Park and Dongkyu Jeon and Sungwoo Cho and Lee, {Gee Eun} and Jeonghun Kim and Moon, {Young hye} and Kim, {Jae Ouk} and Nam, {Jae Sung} and Kim, {Chang Hoon} and Sungmin Moon and Chung, {Youn Wook} and Park, {Man Seong} and Ryu, {Ji Hwan} and Wan Namkung and Lee, {Jae Myun} and Lee, {Min Goo}",

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doi = "10.1016/j.celrep.2022.111117",

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AU - Sim, Ju Ri

AU - Shin, Dong Hoon

AU - Park, Pil Gu

AU - Park, So Hyeon

AU - Bae, Joon Yong

AU - Lee, Youngchae

AU - Kang, Dha Yei

AU - Kim, Ye Jin

AU - Aum, Sowon

AU - Noh, Shin Hye

AU - Hwang, Su Jin

AU - Cha, Hye Ran

AU - Kim, Cheong Bi

AU - Ko, Si Hwan

AU - Park, Sunghoon

AU - Jeon, Dongkyu

AU - Cho, Sungwoo

AU - Lee, Gee Eun

AU - Kim, Jeonghun

AU - Moon, Young hye

AU - Kim, Jae Ouk

AU - Nam, Jae Sung

AU - Kim, Chang Hoon

AU - Moon, Sungmin

AU - Chung, Youn Wook

AU - Park, Man Seong

AU - Ryu, Ji Hwan

AU - Namkung, Wan

AU - Lee, Jae Myun

AU - Lee, Min Goo

PY - 2022/7/19

Y1 - 2022/7/19

N2 - 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).

AB - 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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DO - 10.1016/j.celrep.2022.111117

M3 - Article

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AN - SCOPUS:85134741257

SN - 2211-1247

VL - 40

JO - Cell Reports

JF - Cell Reports

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M1 - 111117

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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