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Engineered ACE2-Fc counters murine lethal SARS-CoV-2 infection through direct neutralization and Fc-effector
Yaozong Chen1, Lulu Sun2, Irfan Ullah3
1Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4712, USA.
Science Advances
|July 20, 2022
Summary
Engineered soluble angiotensin-converting enzyme 2 (ACE2) variants show potent neutralization of SARS-CoV-2, including Omicron. These enhanced ACE2-Fc antivirals also leverage Fc-effector functions for improved therapeutic efficacy against severe acute respiratory syndrome coronavirus 2.
Area of Science:
- Virology
- Immunology
- Biochemistry
Background:
- Soluble angiotensin-converting enzyme 2 (ACE2) is a potential antiviral for coronaviruses.
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes ACE2 for cell entry.
- Developing effective SARS-CoV-2 antivirals is critical.
Purpose of the Study:
- To engineer enhanced bivalent ACE2-Fc fusion proteins targeting SARS-CoV-2.
- To improve ACE2 receptor binding and neutralize viral variants.
- To evaluate the therapeutic potential of these engineered variants in vivo.
Main Methods:
- Structure-guided design of ACE2-Fc variants with specific mutations.
- Biochemical assays to assess receptor binding and enzymatic activity.
- In vitro neutralization assays against SARS-CoV-2 variants of concern.
- In vivo efficacy studies in a K18-hACE2 mouse model.
Main Results:
- Engineered ACE2-Fcs demonstrated up to 12-fold enhanced binding to the SARS-CoV-2 receptor binding domain.
- The lead variant M81 potently neutralized SARS-CoV-2 variants, including Omicron, with subnanomolar IC50.
- Fc-effector functions (ADCC, phagocytosis, complement deposition) were confirmed.
- Fc-enhanced ACE2-Fc provided significant protection and survival benefits in a lethal SARS-CoV-2 mouse model.
Conclusions:
- Engineered ACE2-Fc fusion proteins are potent SARS-CoV-2 antivirals.
- Enhanced binding and Fc-effector functions contribute to therapeutic efficacy.
- Soluble ACE2-based antivirals represent a promising therapeutic strategy against coronaviruses.
