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

Remesh, S. G.; Merz, G. E.; Britol, A. F.; Chio, U. S.; Rizo, A. N.; Pospiech, T. H.; Lui, I.; Laurie, M. T.; Glasgow, J.; Le, C. Q.; Zhang, Y.; Diwanji, D.; Hernandez, E.; Lopez, J.; Pawar, K. I.; Pourmal, S.; Smith, A. M.; Zhou, F.; QBI Coronavirus Research Group Structural Biology Consortium,; DeRisi, J.; Kortemme, T.; Rosenberg, O. S.; Glasgow, A.; Leung, K. K.; Wells, J. A.; Verba, K. A.

doi:10.1101/2022.08.09.503400

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bioRxiv · 10.1101/2022.08.09.503400

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

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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-Spike-RBD and prevent viral entry into host cells ("receptor traps"). Here we determine cryo-EM structures of our receptor traps in complex with full length Spike. 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 - 4.2nM) 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.

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Remesh, S. G., Merz, G. E., Britol, A. F., Chio, U. S., Rizo, A. N., Pospiech, T. H., Lui, I., Laurie, M. T., Glasgow, J., Le, C. Q., Zhang, Y., Diwanji, D., Hernandez, E., Lopez, J., Pawar, K. I., Pourmal, S., Smith, A. M., Zhou, F., QBI Coronavirus Research Group Structural Biology Consortium,, DeRisi, J., Kortemme, T., Rosenberg, O. S., Glasgow, A., Leung, K. K., Wells, J. A., Verba, K. A.. 2022-08-10. Computational pipeline provides mechanistic understanding of Omicron variant of concern neutralizing engineered ACE2 receptor traps. https://doi.org/10.1101/2022.08.09.503400

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