tetano
Editor, Senior Moderator
Front Immunol
. 2020 Sep 17;11:570018.
doi: 10.3389/fimmu.2020.570018. eCollection 2020.
Blocking of the High-Affinity Interaction-Synapse Between SARS-CoV-2 Spike and Human ACE2 Proteins Likely Requires Multiple High-Affinity Antibodies: An Immune Perspective
Indu Khatri[SUP] 1 2 [/SUP], Frank J T Staal[SUP] 1 [/SUP], Jacques J M van Dongen[SUP] 1 [/SUP]
Affiliations
Abstract
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 ([SUB]h[/SUB]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 [SUB]h[/SUB]ACE2 (18 interactions), at least 15-fold stronger than between SARS-CoV-1 and [SUB]h[/SUB]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 [SUB]h[/SUB]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 [SUB]h[/SUB]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.
Keywords: ACE2; IgA dimer; SARS-CoV; antibody; binding-affinity; felines; interaction-synapse; interface.
. 2020 Sep 17;11:570018.
doi: 10.3389/fimmu.2020.570018. eCollection 2020.
Blocking of the High-Affinity Interaction-Synapse Between SARS-CoV-2 Spike and Human ACE2 Proteins Likely Requires Multiple High-Affinity Antibodies: An Immune Perspective
Indu Khatri[SUP] 1 2 [/SUP], Frank J T Staal[SUP] 1 [/SUP], Jacques J M van Dongen[SUP] 1 [/SUP]
Affiliations
- PMID: 33042151
- PMCID: PMC7527437
- DOI: 10.3389/fimmu.2020.570018
Abstract
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 ([SUB]h[/SUB]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 [SUB]h[/SUB]ACE2 (18 interactions), at least 15-fold stronger than between SARS-CoV-1 and [SUB]h[/SUB]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 [SUB]h[/SUB]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 [SUB]h[/SUB]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.
Keywords: ACE2; IgA dimer; SARS-CoV; antibody; binding-affinity; felines; interaction-synapse; interface.