Journal Article Epublish
PubMed: 40333723 DOI: 10.3390/molecules30081750
Computational Design and Evaluation of Peptides to Target SARS-CoV-2 Spike-ACE2 Interaction.
Molecules 30(8)
Authors: Saja Almabhouh, Erika Cecon, Florence Basubas, Ruben Molina-Fernandez, Tomasz Maciej Stepniewski, Jana Selent, Ralf Jockers, Amal Rahmeh, Baldo Oliva, Narcis Fernandez-Fuentes
Affiliations
- Structural Bioinformatics Laboratory (GRIB-IMIM), Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
- Institute Cochin, INSERM, CNRS, Université Paris Cité, F-75014 Paris, France.
- Synthetic Biology, Department of Medicine and Life Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
- GPCR Drug Discovery, Hospital del Mar Research Institute, 08003 Barcelona, Spain.
- Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, Aberystwyth SY23 3EE, UK.
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.
MeSH
Cells, Sars-Cov-2, Severe Acute Respiratory Syndrome-Related Coronavirus