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

21 April 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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.


receptor-binding domain
protein-protein interaction
solid-phase synthesis
circular dichroism
ELISA assay

Supplementary materials

Supplementary Material
Copies of HPLC chromatograms and ESI-MS spectra of 1-6, copies of 1H-ES and TOCSY-ES of 6.


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.