SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2
cell biology immunology/immunity molecular biology virology
Authors: Clausen et al
Link to paper: https://www.biorxiv.org/content/10.1101/2020.07.14.201616v1
Journal/ Pre-Print: bioRxiv
Tags: Cell Biology, Immunology/Immunity, Molecular biology, Virology
The receptor binding domain of the SARS-CoV-2 spike protein contains binding sites for both ACE2 and heparan sulfate (HS), and HS binding is required for ACE2 binding
Addition of exogenous heparin, heparin lyases and lung HS all inhibited spike protein binding and infection with S-pseudotype virus and SARS-CoV-2
Docking studies of the receptor binding domain (RBD) of the SARS-CoV-2-S protein indicated a heparan sulfate (HS) binding site adjacent to that of ACE2. Spike ectodomains bound column-bound heparin and HS on several cell lines. ACE2 binding was dependent on HS: binding of spike ectodomains and infection with spike-bearing VSV and SARS-CoV-2 were inhibited by depleting HS availability by addition of HS lyases, unfractionated heparin, non-anticoagulent heparin, lung-derived HS or inactivation of a core HS synthetic enzyme, EXT1. Mutations of enzymes involved in HS modification indicated that the RBD may recognise a specific pattern of sulfation on HS.
Impact for SARS-CoV2/COVID19 research efforts
Understand the virology and/or cell biology of SARS-CoV2/COVID19 - This study indicates that HS may act as a co-receptor for ACE2 binding by SARS-CoV-2 and presents a novel therapeutic strategy by targeting HS adhesion.
In vitro study
Strengths and limitations of the paper
Novelty: This study shows that targeting HS binding by the spike protein can inhibit infection with SARS-CoV-2. An HS binding site on the RBD structure is suggested. It also suggests that level of cellular HS sulfation or sulfation pattern may contribute to ACE2 binding, which may contribute to susceptibility of patients to severe infection.
Standing in the field:Previous literature has suggested cellular HS as a therapeutic target for COVID-19 and drugs such as suramin have been shown to have anti-viral properties. It has also been reported the SARS-CoV-2-S protein undergoes a conformational change upon HS binding. This study builds on current findings by showing that SARS-CoV-2 infection can be decreased by targeting HS binding.
Appropriate statistics: Yes
Viral model used:VSV pseudotype expressing S protein, SARS-CoV-1 and SARS-CoV-2 virus
Translatability:No therapeutic or clinical work was done, but this study does further highlight HS as a viable target for COVID-19 treatment.
Main limitations: In vitro work only