Computational design and evaluation of peptides to target SARS-CoV-2 spike-ACE2 interaction

Almabhouh, Saja; Cecon, Erika; Basubas, Florence; Molina Fernández, Rubén; Stepniewski, Tomasz Maciej, 1988-; Selent, Jana; Jockers, Ralf; Rahmeh, Amal; Oliva Miguel, Baldomero; Fernández Fuentes, Narcís

doi:http://dx.doi.org/10.3390/molecules30081750

Computational design and evaluation of peptides to target SARS-CoV-2 spike-ACE2 interaction

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Almabhouh S, Cecon E, Basubas F, Molina-Fernandez R, Maciej Stepniewski T, Selent J, et al. Computational design and evaluation of peptides to target SARS-CoV-2 spike-ACE2 interaction. Molecules. 2025 Apr 14;30(8):1750. DOI: 10.3390/molecules30081750

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.