Designer Stapled Peptides Mimicking the ACE2 Receptor Blocked SARS-CoV-2 Infection in Lab Tests

Researchers designed four double-stapled peptides based on the ACE2 receptor helix that SARS-CoV-2 uses to enter human cells. Three of four showed potent antiviral activity with IC50 values of 1.9–4.1 μM in ACE2-overexpressing cells. The most effective peptide, NYBSP-1, completely prevented viral damage at 17.2 μM against authentic SARS-CoV-2. The stapled peptides achieved 50–94% helicity versus only 19% for the linear control, and showed no cytotoxicity. Lead peptide NYBSP-4 demonstrated a plasma half-life exceeding 289 minutes.

Four double-stapled peptides were designed based on the ~30 amino acid ACE2 binding helix. Helicity was measured by circular dichroism. Antiviral activity was tested using pseudovirus assays in HT1080/ACE2 and A549/ACE2 cells, then validated against authentic SARS-CoV-2 (US_WA-1/2020) in Vero E6 cells. Cytotoxicity and proteolytic stability in human plasma were also assessed.

This work demonstrates a peptide-based strategy for blocking viral entry by mimicking the host receptor. The stapling technique stabilized the peptide structure, dramatically improving both antiviral activity and resistance to degradation — showcasing a generalizable approach for designing therapeutic peptides against emerging viruses.

Stapled peptides represent an innovative class of therapeutics that bridge the gap between small molecule drugs and large biologics. This work demonstrated that peptide stapling can create stable, potent viral entry inhibitors — a strategy that could be rapidly adapted for future pandemic threats. The approach is particularly valuable because it targets the highly conserved virus-receptor interaction rather than viral proteins that mutate frequently.

All testing was in vitro (cell cultures); no animal or human studies were conducted. The IC50 values are in the micromolar range, which may present challenges for achieving therapeutic concentrations in vivo. The study was conducted early in the pandemic with the original SARS-CoV-2 strain; effectiveness against later variants is unknown.