Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants

Vaccine hesitancy and the emergence of SARS-CoV-2 variants of concern (VOCs) that can escape vaccine-induced immunity underscore the need for new therapeutics. Engineered soluble ACE2 proteins with enhanced affinity for the viral spike (S) protein may function as broad decoys. Using molecular dynamics simulations and functional assays, the authors show that three substitutions in an engineered soluble ACE2 (sACE2 v2.4; T27Y, L79T, N330Y) markedly increase affinity for S from the original WA-1/2020 isolate and multiple VOCs (Alpha, Beta, Gamma, Delta). In K18-hACE2 transgenic mice infected with WA-1/2020 or P.1 (Gamma), both prophylactic and therapeutic dosing of sACE2 v2.4-IgG1 prevented lung vascular injury and edema, key features of SARS/ARDS, and improved survival. These data demonstrate broad in vivo efficacy of an engineered ACE2 decoy against SARS-CoV-2 variants in mice and support its 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