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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
Frontiers in Immunology ( IF 5.7 ) Pub Date : 2020-08-18 , DOI: 10.3389/fimmu.2020.570018
Indu Khatri 1, 2 , Frank J T Staal 1 , Jacques J M van Dongen 1
Affiliation  

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.



中文翻译:

阻断 SARS-CoV-2 刺突与人类 ACE2 蛋白之间的高亲和力相互作用突触可能需要多种高亲和力抗体:免疫视角

由 SARS-CoV-2 引起的 2019 冠状病毒病 (COVID-19) 大流行引发了全球对开发治疗 COVID-19 的疫苗和疗法(包括中和抗体)的渴望。为了开发针对 SARS-CoV-2 的有效治疗抗体,了解病毒和宿主蛋白质之间的相互作用至关重要。人类 ACE2 ( h ACE2) 蛋白是 SARS-CoV 刺突蛋白的关键靶点,使病毒能够粘附到宿主上皮细胞上。蛋白质-蛋白质相互作用的 X 射线晶体结构和生物物理特性揭示了 SARS-CoV-2 和h ACE2之间具有高结合亲和力的大相互作用表面(18 种相互作用),比 SARS-CoV-1 之间至少强 15 倍和h ACE2(八种相互作用)。这表明针对 CoV-1 感染的抗体可能对 CoV-2 不是非常有效。此外,种间比较表明,人和猫的 ACE2 蛋白比狗、雪貂、小鼠和大鼠更接近,Spike 和 ACE2 蛋白之间的结合亲和力存在显着差异。这强化了猫科动物和人类之间有效的 SARS-CoV-2 传播的概念,并且经典动物模型并不最适合评估治疗性抗体。SARS-CoV-2 和h ACE2 (dG−12.4)之间具有强亲和力的大相互作用表面,对开发真正阻止 SARS-CoV-2 粘附和感染的可靠抗体疗法提出了巨大的挑战。我们估计,针对单一表位的单一抗体可能不足以干扰 Spike 和h ACE2 蛋白之间的强相互作用突触。相反,可能需要针对不同表位的高亲和力中和抗体的适当组合,最好是 IgA 类抗体,以在呼吸道和肠道上皮层获得最佳且持久的活性。

更新日期:2020-09-18
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