Stapled ACE2 peptidomimetics designed to target the SARS‐CoV‐2 spike protein do not prevent virus internalization

COVID‐19 is caused by a novel coronavirus called severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Virus cell entry is mediated through a protein‐protein interaction (PPI) between the SARS‐CoV‐2 spike protein and angiotensin‐converting enzyme 2 (ACE2). A series of stapled peptide ACE2 peptidomimetics based on the ACE2 interaction motif were designed to bind the coronavirus S‐protein RBD and inhibit binding to the human ACE2 receptor. The peptidomimetics were assessed for antiviral activity in an array of assays including a neutralization pseudovirus assay, immunofluorescence (IF) assay and in‐vitro fluorescence polarization (FP) assay. However, none of the peptidomimetics showed activity in these assays, suggesting that an enhanced binding interface is required to outcompete ACE2 for S‐protein RBD binding and prevent virus internalization.