Broad Efficacy of a Computationally Designed ACE2 Decoy Against SARS-CoV-2 Omicron Variants and Related Viruses In Vitro and In Vivo

Authors

Brandon Havranek, Thomas Jefferson UniversityFollow
Graeme W. Lindsey, University of Illinois at Urbana-Champaign
Yusuke Higuchi, Kyoto Prefectural University of Medicine, Kyoto, Japan
Yumi Itoh, Osaka University, Osaka, Japan
Tatsuya Suzuki, Osaka University, Osaka, Japan
Toru Okamoto, Osaka University, Osaka, Japan
Atsushi Hoshino, Kyoto Prefectural University of Medicine, Kyoto, Japan
Erik Procko, University of Illinois at Urbana-Champaign
Shahidul M. Islam, University of Illinois at Chicago

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Description

Background: The SARS-CoV-2 omicron variant (B.1.1.529) and its sublineages are currently the dominant variants in the United States accounting for 100% of COVID-19 cases. Problem: The S protein receptor-binding domain (RBD), located in the S1 subunit of the S protein, binds the human angiotensin-converting enzyme 2 (hACE2) leading to S1 shedding and proteolytic processing of S2 that is important for membrane fusion and release of viral RNA. Various neutralizing therapeutics including protein minibinders, peptides, monoclonal antibodies, and nanobodies have been developed to block the critical interaction between the RBD and hACE2. However, these therapeutics are often developed against the S protein of wildtype or a specific variant of SARSCoV- 2, making them highly susceptible to mutational escape.1 Solution: A strategy employed by our group includes using sACE2 (soluble dimeric ACE2 that contains both the protease and dimerization domains) with enhanced S RBD affinity to outcompete native ACE2 expressed on host cells, acting as a ‘decoy’ to block the interaction between the RBD and hACE2 (Figure 1). sACE2 has moderate affinity for the S protein (~20 nM)2. Therefore, sACE2 must be engineered (by introducing affinity enhancing mutations) to bind with tighter affinity to outcompete membrane bound ACE2-S interaction and rival the potency of mAbs. These sACE2 derivatives maintain close similarity to the native ACE2 receptor making them extremely resistant to virus escape. Any mutation in the RBD that limits binding to the sACE2 derivative will likely have reduced binding towards native ACE2 receptors potentially making the virus unfit to propagate.

Publication Date

2-6-2023

Keywords

SARS-CoV-2, omicron, viral escape, recombinant protein therapy, ACE2, decoy

Disciplines

Medicine and Health Sciences

Comments

Presented at the 2023 AOA Research Symposium.

Recommended Citation

Havranek, Brandon; Lindsey, Graeme W.; Higuchi, Yusuke; Itoh, Yumi; Suzuki, Tatsuya; Okamoto, Toru; Hoshino, Atsushi; Procko, Erik; and Islam, Shahidul M., "Broad Efficacy of a Computationally Designed ACE2 Decoy Against SARS-CoV-2 Omicron Variants and Related Viruses In Vitro and In Vivo" (2023). Alpha Omega Alpha Research Symposium Posters. 1.
https://jdc.jefferson.edu/aoa_research_symposium_posters/1