Vaccine hesitancy and the emergence of SARS-CoV-2 variants escaping vaccine-induced immunity highlight the need for new COVID-19 therapeutics. Engineered soluble ACE2 (sACE2) proteins with increased binding affinity for the SARS-CoV-2 spike (S) protein offer potential. This study shows that three amino acid substitutions in sACE2 markedly increased its affinity for the S protein of multiple SARS-CoV-2 variants. Prophylactic and therapeutic injections of the engineered sACE2_2.v2.4-IgG1 in humanized K18-hACE2 mice prevented lung injury and improved survival against SARS-CoV-2 WA-1/2020 and P.1 variants, demonstrating broad *in vivo* efficacy and therapeutic potential.

Lianghui Zhang, Soumajit Dutta, Shiqin Xiong, Matthew Chan, Kui K. Chan, Timothy M. Fan, Keith L. Bailey, Matthew Lindeblad, Laura M. Cooper, Lijun Rong, Anthony F. Gugliuzza, Diwakar Shukla, Erik Procko, Jalees Rehman, Asrar B. Malik