The sequence of human ACE2 is suboptimal for binding the S spike protein of SARS coronavirus 2

Erik Procko

infection (12, (21) (22) (23) (24) . In principle, the virus has limited potential to escape sACE2-40 mediated neutralization without simultaneously decreasing affinity for native ACE2 41 receptors, thereby attenuating virulence. Furthermore, fusion of sACE2 to the Fc region of 42 human immunoglobulin can provide an avidity boost while recruiting immune effector 43 functions and increasing serum stability, an especially desirable quality if intended for 44 prophylaxis (23, 25), and sACE2 has proven safe in healthy human subjects (26) typically yield no more than one coding variant per cell, providing a tight link between 62 genotype and phenotype (32, 33). Cells were then incubated with a subsaturating dilution 63 of medium containing the RBD of SARS-CoV-2 fused C-terminally to superfolder GFP 64 (sfGFP: (34)) ( Fig. 1A) . Levels of bound RBD-sfGFP correlate with surface expression levels 65 of myc-tagged ACE2 measured by dual color flow cytometry. Compared to cells expressing 66 wild type ACE2 (Fig. 1C ), many variants in the ACE2 library fail to bind RBD, while there 67 appeared to be a smaller number of ACE2 variants with higher binding signals (Fig. 1D ). 68