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,Frank J T Staal,Jacques J M Van Dongen

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 (hACE2) 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 hACE2 (18 interactions), at least 15-fold stronger than between SARS-CoV-1 and hACE2 (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 hACE2 (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 hACE2 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.

Highlights

As of June 2020, the coronavirus disease 2019 (COVID-19) pandemic has infected more than six million individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)
The interaction between the angiotensin-converting enzyme 2 (ACE2) protein in humans and the Spike (S) protein in SARS-CoV’s (CoV′sS) is known from the 2003 outbreak [3, 4]. This is in contrast to the related Middle East respiratory syndrome (MERS)-CoV virus, known from the 2012 outbreak [5], which has a S protein, that does not bind to human ACE2 (hACE2), but to dipeptidyl peptidase-4 (DPP4), known as the CD26 receptor [6, 7]
Since the binding affinity of S viral proteins to mouse ACE2 receptors is less than half as compared to humans, non-human primates and cats [69], the antibodies raised in mouse models will not be effective in humans

Summary

INTRODUCTION

As of June 2020, the coronavirus disease 2019 (COVID-19) pandemic has infected more than six million individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). As adherence of SARS-CoV virus to host cells is mediated by interaction of the RBD domain of the viral S protein with host’s ACE2 receptor, the viral S protein becomes a major target for developing the neutralizing antibodies. The CR3022 and CR3014 antibodies were able to 100% neutralize SARS-CoV-1 infection, the same cocktail will not be effective against SARSCoV-2 infection [24] This argument is supported by the larger interface of the CoV2S-hACE2 protein-protein interaction (Figure 1) and >15-fold higher binding affinity of the CoV2ShACE2 interaction [Kd of 8.30E-10 M as compared to 1.20E08 M in CoV1S-hACE2; as calculated by PRODIGY [34]]. IgA should be preferred over IgG-based responses in vaccination strategies and antibody treatment against COVID19 infection

CONCLUDING REMARKS

Findings

DATA AVAILABILITY STATEMENT