- Recombinant angiotensin-converting enzyme 2 (ACE2) was developed as a biologic against acute respiratory distress syndrome and rapidly repositioned as a decoy receptor for SARS-CoV-2 after emergence of COVID-19.
- High-affinity mutagenesis and fusion with IgG-Fc enables recombinant ACE2 to effectively neutralize SARS-CoV-2 in animal models of COVID-19.
- ACE2 decoy receptors neutralize broadly SARS-CoV-2 variants as well as ACE2-utilizing sarbecoviruses.
- Enhancement of Fc effector function has the potential to promote antiviral effects by the clearance of viral particles, cytotoxic elimination of virus-infected cells, and induction of antiviral T cell responses.
- Direct drug delivery to infectious site by liquid aerosol inhalation potentially enhances therapeutic efficacy against COVID-19.
Engineered ACE2 decoy receptors as an alternative strategy to overcome SARS-CoV-2 evolution
- VanBlargan L.A.
- et al.
ACE2 as an enzymatic drug for ARDS and decoy receptor for COVID-19
ACE2 mutagenesis approaches to achieve increased affinity
Directed evolution as an established protein engineering method
|Name||Mutations for affinity|
(mutations for enzyme)
|Length||Fc||KD (nM)||IC50 (μg/ml)||Efficacy for omicron||Animal model, virus strain, delivery time, route and dose||Refs|
|Hamster, Wuhan, post-infection, 20mg/kg i.p.||[|
|3.98||0.068||Validated in in vitro|
|Validated in mice||Hamster and CAG-hACE2 mice, Omicron, post-infection, 20mg/kg i.p.||[|
|Validated in vitro||K18-hACE2 mice, rhesus/cynomolgus macaques, AAV, pre-infection||[|
|Deep mutational scanning|
in in vitro
|K18-hACE2 mice, Wuhan & Gamma, pre-/post-infection, 10 mg/kg i.v., Inhalation 3×||[|
An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2.
|N.D.||K18-hACE2 mice, Wuhan, pre-/post-infection, 12.5 mg/kg i.n., 6.25 mg/kg i.v.||[|
|Multimer ACE2 and others|
5.1 nM (WT)
|Hamster, Wuhan, post-infection, 5/50 mg/kg i.p.||[|
|Ad5-hACE2-transduced/K18-ACE2 mice, Wuhan, pre-/post-infection, 15/30 mg/kg i.v.||[|
|Ad5-hACE2-transduced mice, Wuhan, pre-/post-infection, 50mg/kg i.p.||[|
0.68 nM (WT)
DMS for comprehensive mutagenesis analysis
Computational design with growing sophistication
- Chen Y.
- et al.
- Chen Y.
- et al.
- Chen Y.
- et al.
Fc fusion to manipulate pharmacokinetics, immunological activity, and avidity effect
- Li Y.
- et al.
Dual aspects of ACE2 enzymatic activity on drugs for COVID-19
- Zhang L.
- et al.
Broad-spectrum efficacy against SARS-CoV-2 variants and sarbecoviruses
Antiviral effects of ACE2 decoy receptors in animal models
- Zhang L.
- et al.
Concluding remarks and future perspectives
Declaration of interests
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