Abstract
In 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, exhibiting a high helical folding propensity in aqueous solution. Our best peptide-mimics are able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concentration (IC50) in the nanomolar range upon binding to the virus spike protein with high affinity. These first-in-class blocking peptide mimics represent powerful tools that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19).
Highlights
In 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 receptor plays a central role in cell entry
We demonstrated the non-toxicity of our mimics at concentrations 150 times higher than the IC50 on pulmonary cell lines
We first examined the complex between human Angiotensin Converting Enzyme 2 (hACE2) and the surface spike protein of SARS-CoV-2 (PDB 6m0j)[14] in order to highlight the important contacts and some relevant characteristics of the interacting hACE2 sequence (Fig. 1)
Summary
In 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. Our best peptide-mimics are able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concentration (IC50) in the nanomolar range upon binding to the virus spike protein with high affinity. These first-in-class blocking peptide mimics represent powerful tools that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19). With the goal of preventing the SARS-CoV-2 from infecting human cells, blocking the interaction between hACE2 and the virus spike protein has been validated. An engineered stable mini-protein mimicking three helices of hACE2 to plug SARS-CoV-2 spikes[10] was described, but its capacity to block viral infection was not demonstrated. Several in silico designed peptides were proposed to prevent formation of the fusion core[11,12], first attempts to design a peptide binder derived from hACE2 proved to be a difficult task, leading to mitigated results[13]
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