Angiotensin-converting enzyme 2-based mutant bait effectively reduces COVID-19 in mice
Angiotensin-converting enzyme 2-based mutant bait effectively reduces COVID-19 in mice

Angiotensin-converting enzyme 2-based mutant bait effectively reduces COVID-19 in mice

In a recent study published in Trends in pharmacological sciences, researchers developed a mutant angiotensin-converting enzyme 2 (ACE2) bait that effectively protected human lung epithelium against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by competitively binding to its spike (S) protein. In addition, this mutant decoy enhanced lung damage in mice expressing human ACE2.

Examination: A decoy mutant ACE2 designed to reduce COVID-19. Image credit: Kateryna Kon / Shutterstock

There is an urgent need for new treatments for coronavirus disease 2019 (COVID-19) as the SARS-CoV-2 pandemic continues and new variants emerge. Importantly, COVID-19 vaccines are ineffective in preventing breakthrough infection from new SARS-CoV-2 variants, including its new variant of concern (VoC) Omicron.

S-protein-ACE2 binding establishes SARS-CoV-2 infection on the host cell surface. Blocking this binding on the surface of cells lining the airways, specifically pulmonary alveolar epithelial cells, could effectively prevent SARS-CoV-2 infection.

About the study

In this study, researchers used deep mutagenesis to develop a mutant ACE2, called sACE2.v2.4. This mutant ACE2 was able to bind S protein with a 35-fold higher affinity than wild-type (WT) ACE2 primarily due to its conformational stability.

They tested sACE2.v2.4 in vivo using transgenic mice expressing human ACE2, referred to as K18-hACE2 mice, when using the epithelial-specific K18 protomer (K18-hACE2). SARS-CoV-2 could enter their lung epithelial cells, damaged during COVID-19 infection. Overall, this animal model resembled severe clinical COVID-19, particularly in pulmonary histology and related features.

The researchers also determined the binding affinity of the decoy sACE22.v2.4 immunoglobulin G1 (IgG1) to S protein. They compared its binding affinity to that of clinically used anti-SARS-CoV-2 antibodies.

In particular, similar to the mutant used in the study, monoclonal antibodies (mAbs) neutralize the virus by binding and preventing its docking and uptake of ACE2 on the cell surface; in addition, they promote virus clearance.

Survey results

Similarly constructed ACE2-Fc decoys have successfully contained lung damage and systemic manifestations in hamster models and improved their pulmonary histopathology. Similarly, a study reported that an ACE2 fragment, crystallizable (Fc) bait reduced pulmonary SARS-CoV-2 pseudovirus transduction in K18-hACE2 mice. Due to its Fc component, it had enhanced effector functions that promoted immune clearance of SARS-CoV-2.

The functional assays relevant to pulmonary microvascular injury in clinical acute respiratory distress syndrome (ARDS) and COVID-19, performed during the study, helped researchers study mutant ACE2 receptor decoys much broader than previous studies. Importantly, in this study, Zhang et al. also analyzed endothelial barrier dysfunction, vascular endothelial (VE) cadherin integrity, and pulmonary edema.

They observed that treatment with sACE22.v2.4-IgG1 bait restored the body weight of transgenic mice and the overall survival rate; however, it remained unclear whether this treatment reduced lung epithelial damage. Although after 14 days (rather than seven days) of treatment, the edema fluid disappeared and the lung-wet / dry ratio normalized, suggesting that the lung epithelium plays a central role in the recovery of mice. These results are similar to those reported by previous studies of experimental influenza pneumonia.

Mainly due to the IgG1 Fc fragment of the decoy construct, intravenous infusion of sACE22.v2.4-IgG1 reduced SARS-CoV-2 strains in the lungs of transgenic mice and enabled immune clearance of free virions and SARS-CoV-2 infected cells.

Although bait treatment had no dramatic effect on the lungs of K18-hACE2 mice; there are some plausible concerns regarding the use of a bait to treat COVID-19. For example, they may trigger an autoimmune response or aberrant ACE2 activity or interfere with endogenous ACE2 signaling. These possible problems should be tested in early clinical trials.

Several previous human clinical trials suggest that unwanted hemodynamic changes did not occur with WT-soluble ACE2; likewise, ACE2-like enzymatic activity improved SARS-CoV-2-induced lung damage in mice and hamsters.

Following inoculation of K18-hACE2 mice with the more lethal P.1 variant of SARS-CoV-2, the authors noted that sACE22.v2.4-IgG1 treatment only prevented mortality when administered for 12 hours (not 24 hours). hours) after inoculation, thus recommending early treatment in case of a fatal variant infection.

other than that in vitro, sACE2.v2.4 mutant bound more strongly than WT ACE2 to S of several SARS-CoV-2 variants. When testing against Omicron, in vitro binding of sACE2.v2.4 to Omicron S was strong, in contrast to mAbs, which failed against Omicron due to its highly mutated S protein.


The sACE2.v2.4 bait strategy showed promise against SARS-CoV-2-induced lung damage in mice. Even when used against more transmissible and infectious SARS-CoV-2 VOCs, the lure strategy worked remarkably well, and the sACE2.v2.4 lure bound the Omicron S tightly.

Taken together, the study’s observations suggest that the sACE2.v2.4 bait may remain effective against SARS-CoV-2 variants that have not yet emerged.

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