Peptide foldamer-based inhibitors of the SARS-CoV-2 S protein–human ACE2 interaction

Abstract

The entry of the SARS-CoV-2 virus into a human host cell begins with the interaction between the viral spike protein (S protein) and human angiotensin-converting enzyme 2 (hACE2). Therefore, a possible strategy for the treatment of this infection is based on inhibiting the interaction of the two abovementioned proteins. Compounds that bind to the SARS-CoV-2 S protein at the interface with the alpha-1/alpha-2 helices of ACE2 PD Subdomain I are of particular interest. We present a stepwise optimisation of helical peptide foldamers containing trans-2-aminocylopentanecarboxylic acid residues as the folding-inducing unit. Four rounds of optimisation led to the discovery of an 18-amino-acid peptide with high affinity for the SARS-CoV-2 S protein (K_d = 650 nM) that inhibits this protein–protein interaction with IC₅₀ = 1.3 µM. Circular dichroism and nuclear magnetic resonance studies indicated the helical conformation of this peptide in solution.

Graphical abstract

Keywords:

• COVID-19
• foldamers
• peptides
• helix
• protein-protein interaction
• BLI

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

Data will be made available on request.

Additional information

Funding

The work was financially supported by the National Science Centre, Poland, Grant No. 2020/01/0/ST4/00064 (to Ł.B.). The authors would like to thank Dassault Systems for providing a free 6-month license for the BIOVIA Discovery Studio software package.