Stapled Peptides Targeting SARS-CoV‑2 Spike Protein HR1 Inhibit the Fusion of Virus to Its Cell Receptor

The
pandemic of acute respiratory disease in 2019 caused by highly
pathogenic and infectious SARS-CoV-2 has seriously endangered human
public safety. The 6-HB (HR1–HR2 complex) formation occurring
in the process of spike protein-mediated membrane fusion could serve
as a conserved and potential target for the design of fusion inhibitors.
Based on the HR2 domain of 6-HB, we designed and synthesized 32 stapled
peptides using an all-hydrocarbon peptide stapling strategy. Owing
to the improved proteolytic stability and higher helical contents,
the optimized stapled peptides termed SCH2-1-20 and SCH2-1-27 showed
better inhibitory activities against pseudo and authentic SARS-CoV-2
compared to the linear counterpart. Of note, SCH2-1-20 and SCH2-1-27
were proved to interfere with S protein-mediated membrane fusion.
Structural modeling indicated similar binding modes between SCH2-1-20
and the linear peptide. These optimized stapled peptides could serve
as potent fusion inhibitors in treating and preventing SARS-CoV-2,
and the corresponding SAR could facilitate further optimization.