Synthetic Peptides That Antagonize the Angiotensin-Converting Enzyme-2 (ACE-2) Interaction with SARS-CoV-2 Receptor Binding Spike Protein.
Afsaneh SadremomtazZayana M Al-DahmaniAngel J Ruiz-MorenoAlessandra MontiChao WangTaha AzadJohn C BellNunzianna DotiMarco Antonio Velasco VelazquezDebora de JongJørgen de JongeJolanda M SmitAlexander S S DömlingHarry van GoorMatthew R GrovesPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- sars cov
- angiotensin converting enzyme
- protein protein
- angiotensin ii
- amino acid
- molecular dynamics simulations
- respiratory syndrome coronavirus
- binding protein
- small molecule
- randomized controlled trial
- coronavirus disease
- photodynamic therapy
- mass spectrometry
- gene expression
- risk assessment
- dna binding
- molecular docking
- single molecule
- transcription factor
- deep learning
- reactive oxygen species
- human health
- quantum dots
- replacement therapy
- protein kinase
- signaling pathway