Abstract
Vaccine hesitancy and emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) escaping vaccine-induced immune responses highlight the urgency for new COVID-19 therapeutics. Engineered angiotensin-converting enzyme 2 (ACE2) proteins with augmented binding affinities for SARS-CoV-2 spike (S) protein may prove to be especially efficacious against multiple variants. Using molecular dynamics simulations and functional assays, we show that three amino acid substitutions in an engineered soluble ACE2 protein markedly augmented the affinity for the S protein of the SARS-CoV-2 WA-1/2020 isolate and multiple VOCs: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta). In humanized K18-hACE2 mice infected with the SARS-CoV-2 WA-1/2020 or P.1 variant, prophylactic and therapeutic injections of soluble ACE2 2 .v2.4-IgG1 prevented lung vascular injury and edema formation, essential features of CoV-2-induced SARS, and above all improved survival. These studies demonstrate broad efficacy in vivo of an engineered ACE2 decoy against SARS-CoV-2 variants in mice and point to its therapeutic potential.
【초록키워드】 SARS-CoV-2, Efficacy, ACE2, coronavirus, S protein, B.1.351, SARS-CoV-2 variant, variants of concern, Delta, B.1.617.2, lung, molecular dynamics, Prophylactic, severe acute respiratory syndrome Coronavirus, molecular dynamics simulations, angiotensin-converting enzyme 2, Vaccine hesitancy, COVID-19 therapeutics, variants, binding affinity, Molecular dynamics simulation, Protein, survival, SARS-CoV-2 variants, B.1.1.7, mice, P.1, immune responses, therapeutic, VOCs, edema, Gamma, Alpha, K18-hACE2 mice, Beta, P.1 variant, in vivo, IgG1, affinity, SARS-CoV-2 spike, soluble ACE2, Amino acid, angiotensin, ACE2 protein, Vascular injury, acute respiratory syndrome, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, therapeutic potential, injection, urgency, vaccine-induced immune response, amino acid substitution, vaccine-induced immune responses, humanized, feature, highlight, assays, functional, the S protein, prevented, the SARS-CoV-2, 【제목키워드】 ACE2, SARS-CoV-2 variant, Lung injury, death, mitigate,