An ACE2 fusion protein.

Phase of research

Potential treatment - pre-clinical evidence

How it helps


Drug status


Supporting references
Contradictory references
AI-suggested references
Clinical trials

General information

ACE2-Fc may refer to similar but different fusion proteins serving as SARS-CoV-2 Spike protein decoys.

ACE2-Fc is a name for fusion proteins made of ACE2 residues 18 to 615 fused with human IgG1 Fc at the C-terminus and either a IL-2 secretion signalling peptide at the N-terminus (Huang et al., 2020) or an α-amylase signal peptide for Nicotiana benthamiana expression system (Castilho et al., 2021). ACE2-Fc also refers to another fusion protein expressed in Nicotiana benthamiana system. It is composed of human ACE2 receptor and IgG1 Fc with an (GGGGS)2 linker at ACE2’s C-terminus. The gene for the fusion protein was optimized for the ectopic expression (Siriwattananon et al., 2021). A version of soluble ACE2-Fc was also shown to inhibit the infection by SARS-CoV-2 Spike-pseudotyped viruses corresponding to the emergent B.1.1.7, B.1.351, and P.1 variants in vitro (Hoffmann et al., 2021). The ACE-Fc was also engineered by Ikemura et al. (2022) to reflect changes in the Omicron variant Spike. It was shown to bind Spike RBD of various Spike variants of SARS-CoV-2 and other serbecoviruses and displayed efficacy in animal viral challenges.


sACE2; sol-ACE2-Fc; ACE2 decoy; 3N39v4; 3J113v2; 3J320v3


Supporting references

Link Tested on Impact factor Notes Publication date
Humanized COVID‐19 decoy antibody effectively blocks viral entry and prevents SARS‐CoV‐2 infection
Spike protein ACE2 Protein factor In vitro
Vero E6 cells; HEK293T and H1975 cells (cell phusion assay); SARS-CoV-2/NTU*/TWN/human/2020 strains (*03, 13, 14, 18, 25, or 27) 10.28

Blocked SARS-CoV-2 pseudotyped virus infection at the level of cell entry in vitro (cell culture and lung organoids). It also induced NK cell activation, which might improve viral clearance.

Generation of enzymatically competent SARS‐CoV‐2 decoy receptor ACE2‐Fc in glycoengineered Nicotiana benthamiana
Spike protein ACE2 Protein factor Enzyme assay In vitro
in vitro binding assay; in vitro enzyme assay; Vero E6 cells; SARS-CoV-2 clinical isolate (GenBank MT093571) 3.91

The fusion protein was produced in a plant expression system allowing for protein glycosylation. The ACE2 domain was enzymatically competent. The fusion protein bound SARS-CoV-2 Spike RBD and neutralized the virus in vitro.

Development of Plant-Produced Recombinant ACE2-Fc Fusion Protein as a Potential Therapeutic Agent Against SARS-CoV-2
Spike protein ACE2 Protein factor In vitro
in vitro binding assay; Vero E6 cells; SARS-CoV-2 4.40

The plant-produced (with high yields) protein inhibited SARS-CoV-2 infection in Vero E6 cells with an IC50 of 0.84 μg/ml if added post-infection and 94.66 μg/ml if added at the pre-entry stage of infection.

SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies
Spike protein RNA Small molecule Peptide In vitro Antibody Mixed substance
Caco-2 cells; Vero cells; Sera of vaccinated individuals; (VSV) SARS-CoV-2 Spike-pseudotyped virus (WT, B.1.1.7, B.1.351, ant P.1 variants) 38.64

Displayed efficacy in inhibition of Spike-pseudotyped SARS-CoV-2 in vitro. For the emergent B.1.1.7, B.1.351, and P.1 variants of Spike protein, the efficacy was slightly lower, though.

An engineered ACE2 decoy neutralizes the SARS-CoV-2 Omicron variant and confers protection against infection in vivo
Spike protein ACE2 Spike variant Protein factor Animal model In vitro Antibody
Vero E6/TMPRSS2 cells; CAG-hACE2 transgenic mice; Syrian hamsters; SARS-CoV-2 strains (Wuhan; 2019-nCoV/Japan/TY/WK-521/2020; Omicron; 2019-nCoV/Japan/TY38-873/2021); various sarbecoviral pseudotypes 17.96

The engineered ACE2-based decoy versions 3N39v4, 3J113v2, and 3J320v3 displayed high neutralization capacity against Omicron and other selected variants. The wild type version was capable of neutralization of various SARS-CoV-2 strains, albeit with lower efficacy for most of them compared to the engineered versions. The engineered ACE2-Fc neutralized other serbecoviruses in vitro, as well. The 3N39v4 version of ACE2-Fc was shown to provide significant protection for hamsters and humanized mice from live SARS-CoV-2 Omicron infection. Escape mutations were not observed. 


AI-suggested references

Link Publication date
CD-sACE2 inclusion compounds: An effective treatment for coronavirus disease 2019 (COVID-19).
Reduction of ACE2 serum concentrations by telbivudine in chronic hepatitis B patients.
ACE2 Decoy Receptor Generated by High-throughput Saturation Mutagenesis Efficiently Neutralizes SARS-CoV-2 and Its Prevalent Variants.
Structural insights revealed by crystal structure of B38-CAP, an isoenzyme of carboxypeptidase ACE2, the receptor of SARS-CoV-2
Intranasal gene therapy to prevent infection by SARS-CoV-2 variants
Comparative docking studies to understand the binding affinity of nicotine with soluble ACE2 (sACE2)-SARS-CoV-2 complex over sACE2.
Engineered small extracellular vesicles displaying ACE2 variants on the surface protect against SARS-CoV-2 infection
OM-85 Broncho-Vaxom , a Bacterial Lysate, Reduces SARS-CoV-2 Binding Proteins on Human Bronchial Epithelial Cells.
In Vivo Hematopoietic Stem Cell Gene Therapy for SARS-CoV2 Infection Using a Decoy Receptor
An immunotherapeutic method for COVID-19 patients: a soluble ACE2-Anti-CD16 VHH to block SARS-CoV-2 Spike protein.
A super-potent tetramerized ACE2 protein displays enhanced neutralization of SARS-CoV-2 virus infection
Engineered ACE2 decoy mitigates lung injury and death induced by SARS-CoV-2 variants
Soluble ACE2 as a potential therapy for COVID-19
Bioengineered angiotensin-converting-enzyme-2: a potential therapeutic option against SARS-CoV-2 infection
Killing Two Birds with One Stone by Administration of Soluble ACE2: A Promising Strategy to Treat Both Cardiovascular Diseases and SARS-CoV-2 Infection
Computationally Designed ACE2 Decoy Receptor Binds SARS-CoV-2 Spike (S) Protein with Tight Nanomolar Affinity
Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system.
Characterization of a Novel ACE2-Based Therapeutic with Enhanced Rather than Reduced Activity against SARS-CoV-2 Variants
Effects of angiotensin II receptor blocker usage on viral load, antibody dynamics, and transcriptional characteristics among COVID-19 patients with hypertension
Developing Cytokine Storm-Sensitive Therapeutic Strategy in COVID-19 Using 8P9R Chimeric Peptide and Soluble ACE2
An engineered nano-liposome-human ACE2 decoy neutralizes SARS-CoV-2 Spike protein-induced inflammation in both murine and human macrophages