Abstract
The severe acute respiratory syndrome (SARS)-like coronavirus disease (COVID-19) is caused by SARS-CoV-2 and has been a serious threat to global public health with limited treatment. Cellular heparan sulfate (HS) has been found to bind SARS-CoV-2 spike protein (SV2-S) and co-operate with cell surface receptor angiotensin-converting enzyme 2 (ACE2) to mediate SARS-CoV-2 infection of host cells. In this study, we determined that host cell surface SV2-S binding depends on and correlates with host cell surface HS expression. This binding is required for SARS-Cov-2 virus to infect host cells and can be blocked by heparin lyase, HS antagonist surfen, heparin, and heparin derivatives. The binding of heparin/HS to SV2-S is mainly determined by its overall sulfation with potential, minor contribution of specific SV2-S binding motifs. The higher binding affinity of SV2-S G614 mutant to heparin and upregulated HS expression may be one of the mechanisms underlying the higher infectivity of the SARS-CoV-2 G614 variant and the high vulnerability of lung cancer patients to SARS-CoV-2 infection, respectively. The higher host cell infection by SARS-CoV-2 G614 variant pseudovirus and the increased infection caused by upregulated HS expression both can be effectively blocked by heparin lyase and heparin, and possibly surfen and heparin derivatives too. Our findings support blocking HS-SV2-S interaction may provide one addition to achieve effective prevention and/treatment of COVID-19.
Highlights
The recent emergence of the novel, pathogenic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) worldwide poses a global health emergency (Graham and Baric, 2020)
Reported studies have determined that heparan sulfate (HS) is required for cell surface SARS-CoV-2 spike protein (SV2-S) binding, but it remains unclear if the binding is cell-context dependent including angiotensin-converting enzyme 2 (ACE2) co-expression
The heparinases I–III (HSase) treatment diminished cell surface SV2-S binding and the positive correlation of cell surface ACE2 expression with SV2-S binding (Figures 1C,F,G), showing that SV2-S binding is determined by cell surface HS even if endogenous ACE2 is expressed on cell surface
Summary
The recent emergence of the novel, pathogenic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) worldwide poses a global health emergency (Graham and Baric, 2020). Pathogenesis studies have illuminated that the spike protein of SARS-CoV-2 (SV2-S) binds to angiotensin-converting enzyme 2 (ACE2) on host cell surface for cell entry, and is primed by proteinases, including transmembrane serine protease 2 and cathepsin B and L, to mediate viral and host cell membrane fusion (Hoffmann et al, 2020; Walls et al, 2020a). It remains incompletely understood the molecular mechanisms by which SV2-S mediates SARS-CoV-2 infection of host cells (Hoffmann et al, 2020; Walls et al, 2020a). The SARSCoV-2-S G614 mutant has predominated globally (Walls et al, 2020b; Zhou et al, 2020) and several retrospective cohort studies highlighted that cancer patients are at increased risk for COVID19 severity and fatality (Liang et al, 2020; Mehta et al, 2020; Poortmans et al, 2020; Rogado et al, 2020; Yu et al, 2020; Zhang et al, 2020a,b), while the underlying molecular mechanisms remain largely unknown
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