Identification of a short ACE2-derived stapled peptide targeting the SARS-CoV-2 Spike protein

The design and synthesis of a series of peptide derivatives based on a short ACE2 alpha-helix 1 epitope and subsequent [i - i+4] stapling of the secondary structure resulted in the identification of a 9-mer peptide capable to compete with recombinant ACE2 towards Spike RBD in the micromolar range. Specifically, SARS-CoV-2 Spike inhibitor screening based on colorimetric ELISA assay and structural studies by circular dichroism showed the ring-closing metathesis cyclization being capable to stabilize the helical structure of the 9-mer 34-HEAEDLFYQ-42 epitope better than the triazole stapling via click chemistry. The results are preliminary for the development of small molecule stapled peptides capable of blocking the key ACE2-Spike S1 protein-protein interaction.