Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps,Structure

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Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps
Structure ( IF 4.4 ) Pub Date : 2023-02-17 , DOI: 10.1016/j.str.2023.01.009
Soumya G Remesh ₁ , Gregory E Merz ₂ , Axel F Brilot ₂ , Un Seng Chio ₂ , Alexandrea N Rizo ₂ , Thomas H Pospiech ₂ , Irene Lui ₃ , Mathew T Laurie ₄ , Jeff Glasgow ₃ , Chau Q Le ₃ , Yun Zhang ₃ , Devan Diwanji ₂ , Evelyn Hernandez ₂ , Jocelyne Lopez ₂ , Hevatib Mehmood ₂ , Komal Ishwar Pawar ₂ , Sergei Pourmal ₂ , Amber M Smith ₂ , Fengbo Zhou ₂ , , Joseph DeRisi ₅ , Tanja Kortemme ₆ , Oren S Rosenberg ₇ , Anum Glasgow ₈ , Kevin K Leung ₃ , James A Wells ₉ , Kliment A Verba ₁₀

Affiliation

Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA; QBI Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, San Francisco, CA 94158, USA.
QBI Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
QBI Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; QBI, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94158, USA; The University of California, Berkeley-University of California, San Francisco Graduate Program in Bioengineering, University of California, San Francisco, San Francisco, CA 94158, USA.
QBI Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.
QBI Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, San Francisco, CA 94158, USA; QBI, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA 94158, USA.

The SARS-CoV-2 Omicron variant, with 15 mutations in Spike receptor-binding domain (Spike-RBD), renders virtually all clinical monoclonal antibodies against WT SARS-CoV-2 ineffective. We recently engineered the SARS-CoV-2 host entry receptor, ACE2, to tightly bind WT-RBD and prevent viral entry into host cells (“receptor traps”). Here we determine cryo-EM structures of our receptor traps in complex with stabilized Spike ectodomain. We develop a multi-model pipeline combining Rosetta protein modeling software and cryo-EM to allow interface energy calculations even at limited resolution and identify interface side chains that allow for high-affinity interactions between our ACE2 receptor traps and Spike-RBD. Our structural analysis provides a mechanistic rationale for the high-affinity (0.53–4.2 nM) binding of our ACE2 receptor traps to Omicron-RBD confirmed with biolayer interferometry measurements. Finally, we show that ACE2 receptor traps potently neutralize Omicron and Delta pseudotyped viruses, providing alternative therapeutic routes to combat this evolving virus.

中文翻译：

计算管道提供了对中和工程 ACE2 受体陷阱的 Omicron 关注变体的机制理解

SARS-CoV-2 Omicron 变体在刺突受体结合域 (Spike-RBD) 中有 15 个突变，使得几乎所有针对 WT SARS-CoV-2 的临床单克隆抗体都无效。我们最近设计了 SARS-CoV-2 宿主进入受体 ACE2，以紧密结合 WT-RBD 并防止病毒进入宿主细胞（“受体陷阱”）。在这里，我们确定了与稳定的 Spike 胞外域复合的受体陷阱的冷冻电镜结构。我们开发了一种结合 Rosetta 蛋白质建模软件和冷冻电镜的多模型管道，即使在有限的分辨率下也可以进行界面能量计算，并识别允许 ACE2 受体陷阱和 Spike-RBD 之间高亲和力相互作用的界面侧链。我们的结构分析为我们的 ACE2 受体陷阱与 Omicron-RBD 的高亲和力 (0.53–4.2 nM) 结合提供了机制原理，并通过生物层干涉测量证实。最后，我们证明 ACE2 受体陷阱可有效中和 Omicron 和 Delta 假型病毒，为对抗这种不断进化的病毒提供替代治疗途径。

更新日期：2023-02-17

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