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

Soumya G Remesh; Gregory E Merz; Axel F Brilot; Un Seng Chio; Alexandrea N Rizo; Thomas H Pospiech Jr; Irene Lui; Mathew T Laurie; Jeff Glasgow; Chau Q Le; Yun Zhang; Devan Diwanji; Evelyn Hernandez; Jocelyne Lopez; Hevatib Mehmood; Komal Ishwar Pawar; Sergei Pourmal; Amber M Smith; Fengbo Zhou; QCRG Structural Biology Consortium; Joseph DeRisi; Tanja Kortemme; Oren S Rosenberg; Anum Glasgow; Kevin K Leung; James A Wells; Kliment A Verba

doi:10.1016/j.str.2023.01.009

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

Structure. 2023 Mar 2;31(3):253-264.e6. doi: 10.1016/j.str.2023.01.009. Epub 2023 Feb 17.

Authors

Soumya G Remesh¹, Gregory E Merz², Axel F Brilot², Un Seng Chio², Alexandrea N Rizo², Thomas H Pospiech Jr², Irene Lui³, Mathew T Laurie⁴, Jeff Glasgow³, Chau Q Le³, Yun Zhang³, Devan Diwanji², Evelyn Hernandez², Jocelyne Lopez², Hevatib Mehmood², Komal Ishwar Pawar², Sergei Pourmal², Amber M Smith², Fengbo Zhou²; QCRG Structural Biology Consortium; Joseph DeRisi⁵, Tanja Kortemme⁶, Oren S Rosenberg⁷, Anum Glasgow⁸, Kevin K Leung⁹, James A Wells¹⁰, Kliment A Verba¹¹

Affiliations

¹ 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.
² QBI Coronavirus Research Group Structural Biology Consortium, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
⁵ Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
⁶ 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.
⁷ 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.
⁸ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. Electronic address: ag4522@cumc.columbia.edu.
⁹ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: kevin.leung@ucsf.edu.
¹⁰ 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. Electronic address: jim.wells@ucsf.edu.
¹¹ 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. Electronic address: kliment.verba@ucsf.edu.

Abstract

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.

Keywords: ACE2 receptor traps; Rosetta; SARS-CoV-2 Omicron variant; Spike; cryo-EM; protein therapeutics; pseudovirus neutralization.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Angiotensin-Converting Enzyme 2*
Antibodies, Monoclonal
Antibodies, Neutralizing
COVID-19*
Humans
Protein Binding
SARS-CoV-2

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

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