Inhibition of ACE2‐Spike Interaction by an ACE2 Binder Suppresses SARS‐CoV‐2 Entry

The emergence of SARS‐CoV‐2 variants is a significant concern in developing effective therapeutics and vaccines in the middle of the ongoing COVID‐19 pandemic. Here, we have identified a novel small molecule that inhibited the interactions between SARS‐CoV‐2 spike RBDs and ACE2 by modulating ACE2 without impairing its enzymatic activity necessary for normal physiological functions. Furthermore, the identified compounds suppressed viral infection in cultured cells by inhibiting the entry of ancestral and variant SARS‐CoV‐2. Our study suggests that targeting ACE2 could be a novel therapeutic strategy to inhibit SARS‐CoV‐2 entry into host cells and prevent the development of COVID‐19. Targeting the receptor‐binding domain (RBD) of the SARS‐CoV‐2 spike protein could be limited in inhibiting viral entry via the RBD–ACE2 interaction due to the emerging spike mutations. Instead, targeting ACE2 with a small molecule could suppress the entry of ancestral and variant SARS‐CoV‐2 into the host cells, without impairing the enzymatic activity of ACE2, which is necessary for the physiological function of the host cells.