Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein

Afsaneh Sadremomtaz, Zayana M Al-Dahmani, Angel J Ruiz-Moreno, Alessandra Monti, Chao Wang, Taha Azad, John C Bell, Nunzianna Doti, Marco A Velasco-Velázquez, Debora de Jong, Jørgen de Jonge, Jolanda Smit, Alexander Dömling, Harry van Goor*, Matthew R Groves*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

22 Citaten (Scopus)
101 Downloads (Pure)


The SARS-CoV-2 viral spike protein S receptor-binding domain (S-RBD) binds ACE2 on host cells to initiate molecular events, resulting in intracellular release of the viral genome. Therefore, antagonists of this interaction could allow a modality for therapeutic intervention. Peptides can inhibit the S-RBD:ACE2 interaction by interacting with the protein-protein interface. In this study, protein contact atlas data and molecular dynamics simulations were used to locate interaction hotspots on the secondary structure elements α1, α2, α3, β3, and β4 of ACE2. We designed a library of discontinuous peptides based upon a combination of the hotspot interactions, which were synthesized and screened in a bioluminescence-based assay. The peptides demonstrated high efficacy in antagonizing the SARS-CoV-2 S-RBD:ACE2 interaction and were validated by microscale thermophoresis which demonstrated strong binding affinity (∼10 nM) of these peptides to S-RBD. We anticipate that such discontinuous peptides may hold the potential for an efficient therapeutic treatment for COVID-19.

Originele taal-2English
Pagina's (van-tot)2836-2847
Aantal pagina's12
TijdschriftJournal of Medicinal Chemistry
Nummer van het tijdschrift4
Vroegere onlinedatum30-jul.-2021
StatusPublished - 24-feb.-2022

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