High affinity modified ACE2 receptors protect from SARS CoV 2 infection in hamsters
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 Summary Engineered ACE2 decoy receptor has a therapeutic potential against COVID 19 without viral escape mutation.