Abstract
To date, the current COVID-19 pandemic caused by SARS-CoV-2 has infected 99.2 million while killed 2.2 million people throughout the world and is still spreading widely. The unavailability of potential therapeutics against this virus urges to search and develop new drugs. SARS-CoV-2 enters human cells by interacting with human angiotensin-converting enzyme 2 (ACE2) receptor expressed on human cell surface through utilizing receptor-binding domain (RBD) of its spike glycoprotein. The RBD is highly conserved and is also a potential target for blocking its interaction with human cell surface receptor. We designed short peptides on the basis of our previously reported truncated ACE2 (tACE2) for increasing the binding affinity as well as the binding interaction network with RBD. These peptides can selectively bind to RBD with much higher affinities than the cell surface receptor. Thus, these can block all the binding residues required for binding to cell surface receptor. We used selected amino acid regions (21–40 and 65–75) of ACE2 as scaffold for the
de novo
peptide design. Our designed peptide Pep1 showed interactions with RBD covering almost all of its binding residues with significantly higher binding affinity (−13.2 kcal mol
−1
) than the cell surface receptor. The molecular dynamics (MD) simulation results showed that designed peptides form a stabilized complex with RBD. We suggest that blocking the RBD through
de novo
designed peptides can serve as a potential candidate for COVID-19 treatment after further clinical investigations.