Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants
| Autor: | 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 |
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| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Respiratory Distress Syndrome Protein Conformation SARS-CoV-2 COVID-19 Mice Transgenic Cell Biology Lung Injury Protein Engineering Severe Acute Respiratory Syndrome Antiviral Agents Mice Amino Acid Substitution Drug Discovery Animals Humans Amino Acid Sequence Angiotensin-Converting Enzyme 2 Molecular Biology Protein Binding |
| Zdroj: | Nature chemical biology. 18(3) |
| ISSN: | 1552-4469 |
| Popis: | 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 ACE22.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. |
| Databáze: | OpenAIRE |
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