The article investigates the cell entry mechanisms of SARS-CoV-2, a novel coronavirus causing the global pandemic of COVID-19. The study focuses on the role of the virus surface spike protein, which binds to the human receptor ACE2 (hACE2) through its receptor-binding domain (RBD) and is activated by human proteases. Key findings include: 1. **High hACE2 Binding Affinity**: The RBD of SARS-CoV-2 has a higher binding affinity to hACE2 compared to the RBD of SARS-CoV, facilitating efficient cell entry. 2. **Paradoxical Binding Affinity**: Despite the higher binding affinity of the RBD, the entire SARS-CoV-2 spike has a comparable or lower binding affinity to hACE2 compared to the SARS-CoV spike, suggesting that the RBD is less exposed. 3. **Proteinase Activation**: SARS-CoV-2 entry is preactivated by proprotein convertase furin, reducing dependence on target cell proteases. This preactivation allows SARS-CoV-2 to enter cells more efficiently, particularly in cells with low levels of TMPRSS2 and lysosomal cathepsins. 4. **Immune Evasion**: The hidden RBD in the spike protein contributes to immune evasion by being less accessible and thus evading immune surveillance. These mechanisms likely contribute to the high infectivity and wide spread of SARS-CoV-2, and understanding them is crucial for developing effective intervention strategies. The study highlights the importance of targeting both the potency and evasiveness of SARS-CoV-2 to curb its spread.The article investigates the cell entry mechanisms of SARS-CoV-2, a novel coronavirus causing the global pandemic of COVID-19. The study focuses on the role of the virus surface spike protein, which binds to the human receptor ACE2 (hACE2) through its receptor-binding domain (RBD) and is activated by human proteases. Key findings include: 1. **High hACE2 Binding Affinity**: The RBD of SARS-CoV-2 has a higher binding affinity to hACE2 compared to the RBD of SARS-CoV, facilitating efficient cell entry. 2. **Paradoxical Binding Affinity**: Despite the higher binding affinity of the RBD, the entire SARS-CoV-2 spike has a comparable or lower binding affinity to hACE2 compared to the SARS-CoV spike, suggesting that the RBD is less exposed. 3. **Proteinase Activation**: SARS-CoV-2 entry is preactivated by proprotein convertase furin, reducing dependence on target cell proteases. This preactivation allows SARS-CoV-2 to enter cells more efficiently, particularly in cells with low levels of TMPRSS2 and lysosomal cathepsins. 4. **Immune Evasion**: The hidden RBD in the spike protein contributes to immune evasion by being less accessible and thus evading immune surveillance. These mechanisms likely contribute to the high infectivity and wide spread of SARS-CoV-2, and understanding them is crucial for developing effective intervention strategies. The study highlights the importance of targeting both the potency and evasiveness of SARS-CoV-2 to curb its spread.