Computational design and evaluation of peptides to target SARS-CoV-2 spike-ACE2 interaction
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- dc.contributor.author Almabhouh, Saja
- dc.contributor.author Cecon, Erika
- dc.contributor.author Basubas, Florence
- dc.contributor.author Molina Fernández, Rubén
- dc.contributor.author Stepniewski, Tomasz Maciej, 1988-
- dc.contributor.author Selent, Jana
- dc.contributor.author Jockers, Ralf
- dc.contributor.author Rahmeh, Amal
- dc.contributor.author Oliva Miguel, Baldomero
- dc.contributor.author Fernández Fuentes, Narcís
- dc.date.accessioned 2025-06-13T07:46:50Z
- dc.date.available 2025-06-13T07:46:50Z
- dc.date.issued 2025
- dc.description.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.
- dc.description.sponsorship This work was supported by Agence Nationale de la Recherche (ANR-RA-COVID-19 (ANR-20-COV4-0001 to RJ)) and La Marato (202130). This work was also supported by grant PID2020-113203RB-I00 and “Unidad de Excelencia María de Maeztu” (ref: CEX2018-000792-M), funded by the MCIN and the AEI (DOI: 10.13039/501100011033), the SGR from the Generalitat de Catalunya (ref: 4413015318- J.SELENT/SGR-22), Biotechnology and Biological Science Research Council (BBS/E/IB/230001D), and the Welsh Government under the Ser Cymru III Tackling COVID program (WG#009). S. A. acknowledges the support provided by Erasmus+ for the study program.
- dc.format.mimetype application/pdf
- dc.identifier.citation 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
- dc.identifier.doi http://dx.doi.org/10.3390/molecules30081750
- dc.identifier.issn 1420-3049
- dc.identifier.uri http://hdl.handle.net/10230/70681
- dc.language.iso eng
- dc.publisher MDPI
- dc.relation.ispartof Molecules. 2025 Apr 14;30(8):1750
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-113203RB-I00
- dc.rights © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword ACE2 receptor
- dc.subject.keyword SARS-CoV-2
- dc.subject.keyword Molecular dynamics
- dc.subject.keyword Peptide design
- dc.subject.keyword Pseudotyped viral particles
- dc.subject.keyword Spike protein
- dc.subject.keyword Time-resolved FRET assay
- dc.title Computational design and evaluation of peptides to target SARS-CoV-2 spike-ACE2 interaction
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion