ABSTRACT
In the light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site and have a high helical folding propensity in aqueous solution. Our best peptide mimic binds to the virus spike protein with high affinity and is able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concentration (IC50) in the nanomolar range. This first in class blocking peptide mimic represents a powerful tool that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19). In BriefHelical peptide mimicking H1 helix of hACE2 and composed of only natural amino acids binds to SARS-CoV-2 spike protein with high affinity and blocks human pulmonary cells infection with IC50 in the nM range. HighlightsA peptide mimic of hACE2 designed from H1 helix and composed of only natural amino acids show high helical folding propensity in aqueous media. This peptide mimic binds to virus spike RBD with high affinity (sub-nM range). This peptide mimic blocks SARS-CoV-2 pulmonary cells infection with an IC50 in the nM range. This peptide mimic is devoid of toxicity on pulmonary cells.