tetano
Editor, Senior Moderator
Cell Rep
. 2022 Jul 4;111117.
doi: 10.1016/j.celrep.2022.111117. Online ahead of print.
Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition
Ju-Ri Sim[SUP] 1 [/SUP], Dong Hoon Shin[SUP] 1 [/SUP], Pil-Gu Park[SUP] 2 [/SUP], So-Hyeon Park[SUP] 3 [/SUP], Joon-Yong Bae[SUP] 4 [/SUP], Youngchae Lee[SUP] 1 [/SUP], Dha-Yei Kang[SUP] 1 [/SUP], Ye Jin Kim[SUP] 1 [/SUP], Sowon Aum[SUP] 1 [/SUP], Shin Hye Noh[SUP] 5 [/SUP], Su Jin Hwang[SUP] 2 [/SUP], Hye-Ran Cha[SUP] 2 [/SUP], Cheong Bi Kim[SUP] 2 [/SUP], Si Hwan Ko[SUP] 2 [/SUP], Sunghoon Park[SUP] 2 [/SUP], Dongkyu Jeon[SUP] 3 [/SUP], Sungwoo Cho[SUP] 3 [/SUP], Gee Eun Lee[SUP] 4 [/SUP], Jeonghun Kim[SUP] 4 [/SUP], Young-Hye Moon[SUP] 6 [/SUP], Jae-Ouk Kim[SUP] 6 [/SUP], Jae-Sung Nam[SUP] 7 [/SUP], Chang-Hoon Kim[SUP] 7 [/SUP], Sungmin Moon[SUP] 8 [/SUP], Youn Wook Chung[SUP] 8 [/SUP], Man-Seong Park[SUP] 4 [/SUP], Ji-Hwan Ryu[SUP] 9 [/SUP], Wan Namkung[SUP] 10 [/SUP], Jae Myun Lee[SUP] 11 [/SUP], Min Goo Lee[SUP] 12 [/SUP]
Affiliations
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 Ca[SUP]2+[/SUP] 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).
Keywords: ANO6/TMEM16F; CP: Microbiology; SARS-CoV-2; phosphatidylserine; virus-cell fusion.
. 2022 Jul 4;111117.
doi: 10.1016/j.celrep.2022.111117. Online ahead of print.
Amelioration of SARS-CoV-2 infection by ANO6 phospholipid scramblase inhibition
Ju-Ri Sim[SUP] 1 [/SUP], Dong Hoon Shin[SUP] 1 [/SUP], Pil-Gu Park[SUP] 2 [/SUP], So-Hyeon Park[SUP] 3 [/SUP], Joon-Yong Bae[SUP] 4 [/SUP], Youngchae Lee[SUP] 1 [/SUP], Dha-Yei Kang[SUP] 1 [/SUP], Ye Jin Kim[SUP] 1 [/SUP], Sowon Aum[SUP] 1 [/SUP], Shin Hye Noh[SUP] 5 [/SUP], Su Jin Hwang[SUP] 2 [/SUP], Hye-Ran Cha[SUP] 2 [/SUP], Cheong Bi Kim[SUP] 2 [/SUP], Si Hwan Ko[SUP] 2 [/SUP], Sunghoon Park[SUP] 2 [/SUP], Dongkyu Jeon[SUP] 3 [/SUP], Sungwoo Cho[SUP] 3 [/SUP], Gee Eun Lee[SUP] 4 [/SUP], Jeonghun Kim[SUP] 4 [/SUP], Young-Hye Moon[SUP] 6 [/SUP], Jae-Ouk Kim[SUP] 6 [/SUP], Jae-Sung Nam[SUP] 7 [/SUP], Chang-Hoon Kim[SUP] 7 [/SUP], Sungmin Moon[SUP] 8 [/SUP], Youn Wook Chung[SUP] 8 [/SUP], Man-Seong Park[SUP] 4 [/SUP], Ji-Hwan Ryu[SUP] 9 [/SUP], Wan Namkung[SUP] 10 [/SUP], Jae Myun Lee[SUP] 11 [/SUP], Min Goo Lee[SUP] 12 [/SUP]
Affiliations
- PMID: 35839776
- PMCID: PMC9250890
- DOI: 10.1016/j.celrep.2022.111117
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 Ca[SUP]2+[/SUP] 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).
Keywords: ANO6/TMEM16F; CP: Microbiology; SARS-CoV-2; phosphatidylserine; virus-cell fusion.