Abstract
The receptor-binding domain (RBD) of SARS-CoV-2 spike protein is responsible for the recognition of the Angiotensin-Converting Enzyme 2 (ACE2) receptor in human cells and, thus, plays a critical role in viral infection. The therapeutic value of targeting this interaction has been proven by a sizable body of research investigating antibodies, small proteins, aptamers, and peptides. This study presents a novel peptide that impinges the interaction between RBD and ACE2. Starting from a very large pool of structurally designed peptides extracted from our database, PepI-Covid19, a diverse set of peptides were studied using molecular dynamics simulations. Ten of the most promising were chemically synthesized and validated both in vitro and in a cell-based assay. Our results indicate that one of the peptides (PEP10) exhibited the highest disruption of the RBD/ACE2 complex, effectively blocking the binding of two molecules and consequently inhibiting the SARS-CoV-2 spike-mediated cell entry of viruses pseudotyped with the spike of the D614G, Delta, and Omicron variants. PEP10 can potentially serve as a scaffold that can be further optimized for improved affinity and efficacy.