Abstract
SARS-CoV-2 is the novel coronavirus responsible for the outbreak of COVID-19, a disease that has spread to over 100 countries and, as of the 26th July 2020, has infected over 16 million people. Despite the urgent need to find effective therapeutics, research on SARS-CoV-2 has been affected by a lack of suitable animal models. To facilitate the development of medical approaches and novel treatments, we compared the ACE2 receptor, and TMPRSS2 and Furin proteases usage of the SARS-CoV-2 Spike glycoprotein in human and in a panel of animal models, i.e. guinea pig, dog, cat, rat, rabbit, ferret, mouse, hamster and macaque. Here we showed that ACE2, but not TMPRSS2 or Furin, has a higher level of sequence variability in the Spike protein interaction surface, which greatly influences Spike protein binding mode. Using molecular docking simulations we compared the SARS-CoV and SARS-CoV-2 Spike proteins in complex with the ACE2 receptor and showed that the SARS-CoV-2 Spike glycoprotein is compatible to bind the human ACE2 with high specificity. In contrast, TMPRSS2 and Furin are sufficiently similar in the considered hosts not to drive susceptibility differences. Computational analysis of binding modes and protein contacts indicates that macaque, ferrets and hamster are the most suitable models for the study of inhibitory antibodies and small molecules targeting the SARS-CoV-2 Spike protein interaction with ACE2. Since TMPRSS2 and Furin are similar across species, our data also suggest that transgenic animal models expressing human ACE2, such as the hACE2 transgenic mouse, are also likely to be useful models for studies investigating viral entry.
Highlights
SARS-CoV-2 is the novel coronavirus responsible for the outbreak of COVID-19, a disease that has spread to over 100 countries and, as of the 26th July 2020, has infected over 16 million people
Cryo–electron microscopy analysis of human Angiotensin-Converting Enzyme 2 (ACE2) bound to the Receptor Binding Domain (RBD) of the SARS-CoV-2 S glycoprotein showed that ACE2 is a dimer that
The receptor binding domain (RBD) of the SARS-CoV-2 S protein binds directly to the ACE2 peptidase domain (PD), and analysis of the crystal structure of this complex shows that the interaction is mostly driven by polar interactions (Table 2)
Summary
SARS-CoV-2 is the novel coronavirus responsible for the outbreak of COVID-19, a disease that has spread to over 100 countries and, as of the 26th July 2020, has infected over 16 million people. Since TMPRSS2 and Furin are similar across species, our data suggest that transgenic animal models expressing human ACE2, such as the hACE2 transgenic mouse, are likely to be useful models for studies investigating viral entry. Sequencing of the genome of SARS-CoV-2 has demonstrated that it is closely related to coronaviruses isolated from bats These analyses have shown that the genome of SARS-CoV-2 has 96.1% sequence similarity with SARSr-Ra-BatCoV-RaTG13, identified in Rhinolophus affinis bats captured in Pu’er (China) in 2 0132,4. For this reason, it has been proposed that bats have acted as an ecological reservoir for SARS-CoV-2. This is 10–20 times higher than the affinity between the SARS-Cov S protein and ACE2, which likely explains the high infectivity of SARS-CoV-211
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