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

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 (Kd = 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.
Mesh Terms:
Angiotensin-Converting Enzyme 2, COVID-19, Humans, Peptides, SARS-CoV-2, Spike Glycoprotein, Coronavirus
J Enzyme Inhib Med Chem
Date: Dec. 01, 2023
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