High affinity modified ACE2 receptors prevent SARS-CoV-2 infection
Higuchi, Y.; Suzuki, T.; Arimori, T.; Ikemura, N.; Kirita, Y.; Ohgitani, E.; Mazda, O.; Motooka, D.; Nakamura, S.; Matsuura, Y.; Matoba, S.; Okamoto, T.; Takagi, J.; Hoshino, A.
Show abstract
The SARS-CoV-2 spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor via receptor binding domain (RBD) to enter into the cell and inhibiting this interaction is a main approach to inhibit SARS-CoV-2 infection. We engineered ACE2 to enhance the affinity with directed evolution in 293T cells. Three cycles of random mutation and cell sorting achieved 100-fold higher affinity to RBD than wild-type ACE2. The extracellular domain of modified ACE2 fused to the human IgG1-Fc region had stable structure and neutralized SARS-CoV-2 without the emergence of mutational escape. Therapeutic administration protected hamsters from SARS-CoV-2 infection, decreasing lung virus titers and pathology. Engineering ACE2 decoy receptors with human cell-based directed evolution is a promising approach to develop a SARS-CoV-2 neutralizing drug that has affinity comparable to monoclonal antibodies yet displaying resistance to escape mutations of virus. One Sentence SummaryEngineered ACE2 decoy receptor has a therapeutic potential against COVID-19 without viral escape mutation.
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