In response to our recent publication describing affinity-enhanced, long−half-life ACE2-based receptor traps for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization (1), Liu et al. (2) point to their parallel work showing substrate-dependent peptidase activity of ACE2 active site mutants (3). Understanding the physiologically relevant ACE2 peptidase activity determinants is critical, as several groups are developing ACE2-based receptor traps with intact (4, 5), modestly attenuated (6), or ablated activity (1, 7, 8) to separate the effects of blocking on angiotensin II (Ang II) conversion. Toward this end, we introduced an H345L mutation that is postulated to form part of the oxyanion binding site (9); mutations in the oxyanion hole for zinc metalloproteases (10) are well known to disrupt the tetrahedral oxyanion in the transition state and dramatically … [↵][1]2To whom correspondence may be addressed. Email: jim.wells{at}ucsf.edu. [1]: #xref-corresp-1-1