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

The SARS-CoV-2 viral spike protein S receptorbinding
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 SRBD:
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.