A new ACE2 decoy mechanism efficiently neutralizes a variety of Covid-19 variants, including Omicron strains. With the continuous evolution of the SARS-CoV-2 virus over the last three years, the pathogen has become more efficient at infecting our cells and evading our immune defenses. One crucial aspect of this efficiency is affinity to the ACE2 receptor, a major selection criterion in virus evolution.

The ACE2 decoy mimics the host cell ACE2, similarly engaging the virus and inhibiting viral entry to a real cell. Using receptors as decoys is not a novel concept. In connection to SARS-CoV-2, ACE2 decoys were tested against closely related viruses, SARS-1 and HIV, in recent decades. The decoy did not come to fruition against these viruses for myriad reasons. For SARS-1, the strategy showed some signs of reduced symptoms in mouse models, but the outbreak calmed before further animal and human testing could continue. For HIV, sufficient efficacy was never established.

In late 2019, the same research team led by Dr. Josef Penninger behind the SARS-1 experiments conducted similar tests against SARS-CoV-2, though the strategy seemed to have little effect on reducing the severity of Covid-19. More recently, the mechanism is described in a study by Torchia et al. in Boston, this time with more promising results. Here we discuss their results and how this new mechanism could impact Covid-19 treatment moving forward.

ACE2 decoys potently neutralize antibody-resistant SARS-CoV-2 variants, including Omicron

The thought behind ACE2 decoys is similar to that of monoclonal antibody treatments. Administered antibodies latch onto the circulating virus in the patient, typically in the receptor-binding domain, preventing the virus from further infecting host cells.

While an antibody may go on to neutralize itself or by flagging host immune defenses, ACE2 decoys focus on the first half of the process. ACE2 decoy receptors are recombinant soluble forms of ACE2 protein that could bind the virus and inhibit further infection. All versions of SARS-CoV-2 bind ACE2, regardless of mutation, suggesting ACE2 decoys may have a broad activity profile compared to earlier failed monoclonal antibodies.

The ACE2 decoy performed well against SARS-CoV-2 and its variants. While efficacy was moderately worse against the Wuhan strain than several monoclonal antibody treatments, the ACE2 decoy outperformed all monoclonal antibody treatments against the authentic Omicron virus.

Rational design of ACE2-Fc fusions to identify optimal design parameters

The researcher’s next question was how the design of the ACE2 decoy impacted spike protein binding. The ACE2 decoy may contain three of four distinct domains. All ACE2 decoys contain the Fc constant domain. This is the stalk of the ACE2 protein required for structural integrity and often engages immune effector functions. All ACE2 decoys also contain a membrane-distal peptidase domain (PD), which cleaves and inactivates angiotensin-II, a common effector molecule.

The other two domains are a membrane-proximal collectrin-like domain (CLD) that mediates ACE2 homodimerization and a linker domain when the CLD is not present. Torchia et al. developed four structures for their ACE2 decoys.

The PD contains the ACE2 binding site for the virus receptor-binding domain, bringing into question the efficiency of binding given the structure of the ACE2 decoy.

The structure of an ACE2 decoy affects its apparent binding affinity to the S-protein trimer

The researchers compared the apparent binding affinities for the ACE2 decoys to test the structural concerns. The structure with the highest affinity against the S protein trimer was PD-Fc, which is the structure lacking CLD entirely, though the CLD-involved structure had the highest association with the virus receptor-binding domain.

Against SARS-CoV-2 pseudovirus, the PD-CLD-Fc structure outperformed all other structures in reducing the relative infection percentage to zero. In fact, the PD-Fc structure, which boasted the highest affinity, reached zero percent relative infection last among the four, suggesting that more factors are involved in virus binding and neutralization than just affinity.

Inclusion of the ACE2 CLD is necessary for activity against SARS-CoV-2 in hamsters

The researchers then compared the antiviral activities of the differing ACE2 decoy structures in live animal models, namely Syrian hamsters. Not only was the ACE2 decoy that included CLD fought against disease severity in the hamsters in the form of significant weight loss, but the CLD-inclusive structure reduced nasal viral titers by 100-fold, whereas the rest did not record a statistically significant result.

Including the CLD also improves apparent S-protein affinity, improves serum half-life, and enhances viral neutralization.


While these results are promising, we must counterbalance our expectations of the ACE2 decoy with the earlier studies from late 2019. It is unclear why the mechanism worked now, but not then. Perhaps the decoy is effective in mice and hamster models, but not in humans. Further examination is in order before declaring this the latest effective treatment for Covid-19. We need to know its efficacy in human patients and its performance against the latest variants of SARS-CoV-2, such as XBB.1.5.

A virological concern I raise is one of stoichiometry. Can a treatment dose of ACE2 decoys deliver enough ACE2 to cover all the spike trimers on enough virus particles to make a difference? Another concern is that the virus will evolve to find a way around it. HIV likely did something similar and we all know the rapid degree to which SARS-CoV-2 mutates to avoid neutralization. All this to say, similar strategies have not worked in the past with similar viruses, and there are many hurdles ahead. We can hope this treatment overcomes these obstacles, but I would not advise holding your breath.