Most current treatments for SARS-CoV-2 infection involve the use of antibodies to neutralize the virus. However, these antibodies have been found to be less effective for some variants, such as Omicron, as the virus rapidly mutates to avoid neutralization. Researchers at Osaka University and Kyoto Prefectural University of Medicine engineered a decoy ACE2 receptor to neutralize the virus, and found that the decoy was effective against the Omicron variant despite its spike protein mutations.
The engineered ACE2 protein is designed to have a high affinity to the spike protein so that the virus will bind to the decoy instead of the natural ACE2 entryway into cells. The researchers had previously shown that decoy ACE2 receptors are effective against both the original virus strain and variants including Alpha, Beta and Gamma. The Omicron variant includes 15 mutations in the receptor-binding domain (RBD) of the spike protein, which have been shown to help it evade neutralization by therapeutic monoclonal antibodies. The effectiveness of the decoy against Omicron was assessed through several methods, including neutralization assays and creation of a homology model for a complex between the Omicron RBD and decoy protein. Additionally, the researchers infected Vero E6 cells with the Omicron virus in the presence of the engineered ACE2, and further infected Syrian hamsters and mice before treating them with the decoy.
The results of the team’s experiment showed that the ACE2 decoy had no loss of affinity due to the Omicron RBD mutations, and that the engineered receptor could protect against Omicron infection in the same way it protected cells against the original Wuhan strain. Hamsters treated with the engineered ACE2 showed significantly reduced levels of viral RNA in their lungs 5 days after infection compared with those that did not receive treatment, and mice that received the decoy treatment had an improved chance of survival compared to untreated mice after 15 days. Neutralization assays showed that ACE2 is not only effective for neutralizing the original strain and Omicron, but also many other variants from Alpha to Mu, as well as some other sarbecoviruses. A deep mutational analysis showed that the engineered ACE2 can effectively prevent escape for each single-residue mutation found in the Omicron RBD. The research was published in Science Translational Medicine.
“The results were very clear. The engineered ACE2 effectively neutralized the Omicron variant of SARS-CoV-2, to a level comparable to that seen with the original Wuhan variant,” said senior author Atsushi Hoshino. “Our findings suggest that ACE2 is a useful therapeutic option for treating a wide variety of SARS-CoV-2 variants, including Omicron.”
Because the engineered ACE2 was found to be able to neutralize other viruses related to SARS-CoV-2, including those that typically affect animals, it is possible that this decoy approach could be beneficial for managing future disease outbreaks, the researchers said.