tetano
Editor, Senior Moderator
Cell Discov
. 2020 Nov 4;6(1):80.
doi: 10.1038/s41421-020-00222-5.
Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro
Qi Zhang[SUP] 1 [/SUP], Catherine Zhengzheng Chen[SUP] 2 [/SUP], Manju Swaroop[SUP] 2 [/SUP], Miao Xu[SUP] 2 [/SUP], Lihui Wang[SUP] 1 [/SUP], Juhyung Lee[SUP] 1 [/SUP], Amy Qiu Wang[SUP] 2 [/SUP], Manisha Pradhan[SUP] 2 [/SUP], Natalie Hagen[SUP] 2 [/SUP], Lu Chen[SUP] 2 [/SUP], Min Shen[SUP] 2 [/SUP], Zhiji Luo[SUP] 2 [/SUP], Xin Xu[SUP] 2 [/SUP], Yue Xu[SUP] 1 [/SUP], Wenwei Huang[SUP] 2 [/SUP], Wei Zheng[SUP] 2 [/SUP], Yihong Ye[SUP] 3 [/SUP]
Affiliations
Abstract
The cell entry of SARS-CoV-2 has emerged as an attractive drug repurposing target for COVID-19. Here we combine genetics and chemical perturbation to demonstrate that ACE2-mediated entry of SARS-Cov and CoV-2 requires the cell surface heparan sulfate (HS) as an assisting cofactor: ablation of genes involved in HS biosynthesis or incubating cells with a HS mimetic both inhibit Spike-mediated viral entry. We show that heparin/HS binds to Spike directly, and facilitates the attachment of Spike-bearing viral particles to the cell surface to promote viral entry. We screened approved drugs and identified two classes of inhibitors that act via distinct mechanisms to target this entry pathway. Among the drugs characterized, Mitoxantrone is a potent HS inhibitor, while Sunitinib and BNTX disrupt the actin network to indirectly abrogate HS-assisted viral entry. We further show that drugs of the two classes can be combined to generate a synergized activity against SARS-CoV-2-induced cytopathic effect. Altogether, our study establishes HS as an attachment factor that assists SARS coronavirus cell entry and reveals drugs capable of targeting this important step in the viral life cycle.
. 2020 Nov 4;6(1):80.
doi: 10.1038/s41421-020-00222-5.
Heparan sulfate assists SARS-CoV-2 in cell entry and can be targeted by approved drugs in vitro
Qi Zhang[SUP] 1 [/SUP], Catherine Zhengzheng Chen[SUP] 2 [/SUP], Manju Swaroop[SUP] 2 [/SUP], Miao Xu[SUP] 2 [/SUP], Lihui Wang[SUP] 1 [/SUP], Juhyung Lee[SUP] 1 [/SUP], Amy Qiu Wang[SUP] 2 [/SUP], Manisha Pradhan[SUP] 2 [/SUP], Natalie Hagen[SUP] 2 [/SUP], Lu Chen[SUP] 2 [/SUP], Min Shen[SUP] 2 [/SUP], Zhiji Luo[SUP] 2 [/SUP], Xin Xu[SUP] 2 [/SUP], Yue Xu[SUP] 1 [/SUP], Wenwei Huang[SUP] 2 [/SUP], Wei Zheng[SUP] 2 [/SUP], Yihong Ye[SUP] 3 [/SUP]
Affiliations
- PMID: 33298900
- DOI: 10.1038/s41421-020-00222-5
Abstract
The cell entry of SARS-CoV-2 has emerged as an attractive drug repurposing target for COVID-19. Here we combine genetics and chemical perturbation to demonstrate that ACE2-mediated entry of SARS-Cov and CoV-2 requires the cell surface heparan sulfate (HS) as an assisting cofactor: ablation of genes involved in HS biosynthesis or incubating cells with a HS mimetic both inhibit Spike-mediated viral entry. We show that heparin/HS binds to Spike directly, and facilitates the attachment of Spike-bearing viral particles to the cell surface to promote viral entry. We screened approved drugs and identified two classes of inhibitors that act via distinct mechanisms to target this entry pathway. Among the drugs characterized, Mitoxantrone is a potent HS inhibitor, while Sunitinib and BNTX disrupt the actin network to indirectly abrogate HS-assisted viral entry. We further show that drugs of the two classes can be combined to generate a synergized activity against SARS-CoV-2-induced cytopathic effect. Altogether, our study establishes HS as an attachment factor that assists SARS coronavirus cell entry and reveals drugs capable of targeting this important step in the viral life cycle.