ACE2 models of frequently contacted animals provide clues of their SARS-CoV-2 S protein affinity and viral susceptibility.

The outbreak of atypical pneumonia (coronavirus disease 2019 [COVID-19]) has been a global pandemic and has caused severe losses to the global economy. The virus responsible for COVID-9, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has a spike glycoprotein (S protein) that binds angiotensin-converting enzyme 2 (ACE2) present on host cell membranes to gain entry. Based on the full-length human ACE2 cryo-EM structure, we generated homology models of full-length ACE2 proteins from various species (gorilla, monkey, pig, bovine, sheep, cat, dog, mouse, and rat). Although these ACE2 molecules were found to share similar overall structures, their S-ACE2 interface residues differed. These differences likely result in variations in the ACE2 binding affinities to the SARS-CoV-2 S protein. The highest affinities are predicted for human, gorilla, and monkey, while mouse and rat ACE2 are predicted to have the lowest affinities. Cat ACE2 is predicted to have a lower S protein affinity than dog ACE2. Although affinity is not the only factor that affects viral susceptibility, it is one of the most important factors. Thus, we believe that care should be taken with these animals to prevent the spread of SARS-CoV-2 among animal and human populations.