The pandemic of Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2 has induced global eagerness to develop vaccines and therapeutics for treating COVID-19, including neutralizing antibodies. To develop effective therapeutic antibodies against SARS-CoV-2, it is critical to understand the interaction between viral and host’s proteins. The human ACE2 ( h ACE2) protein is the crucial target for the SARS-CoV’s Spike protein that allows the virus to adhere to host epithelial cells. X-ray crystal structures and biophysical properties of protein-protein interactions reveal a large interaction surface with high binding-affinity between SARS-CoV-2 and h ACE2 (18 interactions), at least 15-fold stronger than between SARS-CoV-1 and h ACE2 (eight interactions). This suggests that antibodies against CoV-1 infection might not be very efficient against CoV-2. Furthermore, interspecies comparisons indicate that ACE2 proteins of man and cat are far closer than dog, ferret, mouse, and rat with significant differences in binding-affinity between Spike and ACE2 proteins. This strengthens the notion of productive SARS-CoV-2 transmission between felines and humans and that classical animal models are not optimally suited for evaluating therapeutic antibodies. The large interaction surface with strong affinity between SARS-CoV-2 and h ACE2 (dG−12.4) poses a huge challenge to develop reliable antibody therapy that truly blocks SARS-CoV-2 adherence and infection. We gauge that single antibodies against single epitopes might not sufficiently interfere with the strong interaction-synapse between Spike and h ACE2 proteins. Instead, appropriate combinations of high-affinity neutralizing antibodies against different epitopes might be needed, preferably of IgA-class for optimal and prolonged activity at epithelial layers of respiratory and intestine tracts.
【저자키워드】 ACE2, antibody, SARS-CoV, felines, interface, interaction-synapse, binding-affinity, IgA dimer, 【초록키워드】 COVID-19, neutralizing antibody, antibodies, SARS-CoV-2, Vaccine, pandemic, therapy, Neutralizing antibodies, spike, Human, Infection, animal model, Proteins, virus, SARS-CoV-1, human ACE2, X-ray, Protein, SARS-CoV-2 transmission, comparison, intestine, therapeutic, epithelial cells, crystal structure, epitope, epithelial, Critical, protein-protein interaction, interactions, Combination, Interaction, ACE2 protein, significant difference, ACE2 proteins, treating COVID-19, block, Host, effective, single antibody, classical, develop, caused, eight, interfere, adhere, 【제목키워드】 SARS-CoV-2, spike, Human, Multiple, blocking,