Viral Cell Entry

Viruses require entry into host cells for replication. This process involved attachment of the virus to host cell surface receptors, entry into the cell by endocytosis, and viral uncoating to release the viral genome into the cytoplasm.

Research Areas
Literature (2)

Viral Cell Entry Product Areas

Mechanisms of SARS-CoV-2 Cell Entry

Entry of SARS-CoV-2, the coronavirus that causes COVID-19, into host cells is mediated by binding of spike (S) protein to ACE2, expressed on the host cell surface. The S protein on the surface of SARS-CoV-2 is the largest protein within the virus and is heavily glycosylated. It consists of S1 and S2 domains, responsible for host cell binding and membrane fusion, respectively. The S protein forms extended trimeric structures that give this coronavirus its classical 'crown' shape, and disruption of S protein glycosylation has been shown to impair viral cell entry.

A key difference between the S protein on SARS-CoV-2 and SARS-CoV, the cause of a previous outbreak of severe acute respiratory syndrome (SARS) in 2002-2004, is the presence of a cleavage site for furin at the SARS-CoV-2 S1/S2 boundary. This differs from SARS-CoV, where S1/S2 cleavage is catalyzed by cathepsins (Figure 1). This difference is thought to be a factor in enhanced infectivity of SARS-CoV-2 compared to SARS-CoV, as the furin cleavage sequence fits the 'C-end rule' (CendR), by generation of RRAR binding motif at the C-terminal of S protein, enabling binding of the S protein to neuropilin-1 (NRP1). NRP1 is a membrane-bound co-receptor for VEGF and semaphorin receptor tyrosine kinase families, the expression of which promotes infection of SARS-CoV-2 in human cell lines. The NRP1 antagonist EG 00229 (Cat. No. 6986) inhibits NRP1-S binding and reduces infectivity in vitro.

Comparison of SARS-CoV-2 and SARS-CoV viral cell entry mechanisms

Figure 1: Comparison of viral cell entry mechanisms of SARS-CoV-2 and SARS-CoV, showing SARS-CoV-2 S protein binding to NRP1.

ACE2 is a transmembrane protease and its primary function is to cleave vasoactive peptides of the renin-angiotensin system. The S protein receptor binding domain (RBD) in the S1 ectodomain binds to the extracellular enzymatic domain of ACE2, resulting in endocytosis and translocation of the virus and ACE2 into the host cell. For both SARS-CoV and SARS-CoV-2, priming of the S2 domain is required for fusion to the host cell. This is performed by TMPRSS2, a host serine protease. TMPRSS2 is coexpressed with ACE2 on human bronchial epithelial cells, a key site of SARS-CoV-2 infection in COVID-19. It has been shown that camostat (Cat. No. 3193), an orally active non-selective protease inhibitor, can partially block entry of SARS-COV-2 into lung cells in vitro, by inhibiting TMPRSS2.

Other coronaviruses utilize different transmembrane proteases as their host cell receptor, for example MERS-CoV binds to dipeptidyl peptidase 4 (DPP-IV; CD26) and HCoV-229E binds to aminopeptidase N.

Following fusion to the host cell membrane, the viral genome is released into the cytoplasm. At this point the virus co-opts the transcription and translation machinery of the host cell to replicate itself.

Literature for Viral Cell Entry

Tocris offers the following scientific literature for Viral Cell Entry to showcase our products. We invite you to request* or download your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.


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