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bioRxiv · 10.1101/2021.12.21.473668

Engineered High-Affinity ACE2 Peptide Mitigates ARDS and Death Induced by Multiple SARS-CoV-2 Variants

Zhang, L.·Dutta, S.·Xiong, S.·Chan, M.·Chan, K. K.·Fan, T. M.·Bailey, K. L.·Lindeblad, M.·Cooper, L. M.·Rong, L.·Gugliuzza, A. F.·Shukla, D.·Procko, E.·Rehman, J.·Malik, A. B.
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Abstract

Vaccine hesitancy and continuing emergence of SARS-CoV-2 variants of concern that may escape vaccine-induced immune responses highlight the urgent need for effective COVID-19 therapeutics. Monoclonal antibodies used in the clinic have varying efficacies against distinct SARS-CoV-2 variants; thus, there is considerable interest in engineered ACE2 peptides with augmented binding affinities for SARS-CoV-2 Spike protein. These could have therapeutic benefit against multiple viral variants. Using molecular dynamics simulations, we show how three amino acid substitutions in an engineered soluble ACE2 peptide (sACE22.v2.4-IgG1) markedly increase affinity for the SARS-CoV-2 Spike (S) protein. We demonstrate high binding affinity to S protein of the early SARS-CoV-2 WA-1/2020 isolate and also to multiple variants of concern: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) SARS-CoV-2 variants. In humanized K18-hACE2 mice, prophylactic and therapeutic administration of sACE22.v2.4-IgG1 peptide prevented acute lung vascular endothelial injury and lung edema (essential features of ARDS) and significantly improved survival after infection by SARS-CoV-2 WA-1/2020 as well as P.1 variant of concern. These studies demonstrate for the first time broad efficacy in vivo of an ACE2 decoy peptide against multiple SARS-CoV-2 variants and point to its therapeutic potential.

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Zhang, L., Dutta, S., Xiong, S., Chan, M., Chan, K. K., Fan, T. M., Bailey, K. L., Lindeblad, M., Cooper, L. M., Rong, L., Gugliuzza, A. F., Shukla, D., Procko, E., Rehman, J., Malik, A. B.. 2021-12-22. Engineered High-Affinity ACE2 Peptide Mitigates ARDS and Death Induced by Multiple SARS-CoV-2 Variants. https://doi.org/10.1101/2021.12.21.473668

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