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.
journal_name
Cell Discovjournal_title
Cell discoveryauthors
Zhang Q,Chen CZ,Swaroop M,Xu M,Wang L,Lee J,Wang AQ,Pradhan M,Hagen N,Chen L,Shen M,Luo Z,Xu X,Xu Y,Huang W,Zheng W,Ye Ydoi
10.1038/s41421-020-00222-5subject
Has Abstractpub_date
2020-11-04 00:00:00pages
80issue
1issn
2056-5968pii
10.1038/s41421-020-00222-5journal_volume
6pub_type
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