Infectivity of SARS-CoV-2 is regulated by three sites on the spike protein: a receptor binding motif (RBM), a subunit (S)1/S2 cleavage site acted upon by the host protease furin, and an S2’ cleavage site acted upon by host protease TMPRSS2. The RBM of the spike protein binds to angiotensin converting enzyme 2 (ACE2) that is highly expressed in cells of the lower respiratory tract. Cleavage of the S1/S2 site by furin liberates a RRAR sequence that is C-terminal in the S1 domain that subsequently binds to neuropilin-1 receptors expressed in respiratory and olfactory epithelial cells. Additionally, cleavage at the S1/S2 site enables a structural change that allows further proteolytic processing by TMPRSS2 that is essential for membrane fusion.
The relative contribution of each site to SARS-CoV-2 infectivity and progression to COVID-19 progression has been the subject of debate. All three sites on the spike protein are potential sites of therapeutic intervention. We sought to generate antibodies with fine specificity to each of these sites that could be used to study the mechanisms of virus infection and serve as potential therapeutic antibody leads.
In Summary, we’ve described three unique functional domain-specific antibodies to the CoV-2 spike protein. Their fine specificity is shown by sensitivity of binding to different spike protein constructs. The ability of the antibodies to impact spike protein function is shown by inhibition of AC2 Binding, furin cleavage, and Pseudovirus infectivity. The antibodies can serve as tools to dissect the mechanism of SARS-CoV-2 infectivity and as potential leads for COVID-19 therapeutics.
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We invite you to download our poster that details this research study, including our antibody discovery strategy as well as the Spike protein reagents, screening assay formats, and more that we utilized.
John S. Kenney, Kurt DeShayes, Catherine Vo, Emmeline Truong, Rick Chang, Opel Arenas, Shyairra Dodd, Huda Abushanab, Ron Gamatero, Edgar Rodriguez, Glen Lin, Leonel Santibanez-Vargas, Emily Keshner, Keerthi Sindhu, and Joshua K. Lowitz
Published: May 11, 2021, Presented at PEGS Boston 2021