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Review
. 2022 Sep;28(9):e3409.
doi: 10.1002/psc.3409. Epub 2022 Feb 26.

Stapled peptides as potential inhibitors of SARS-CoV-2 binding to the hACE2 receptor

Susan Tzotzos  1
Affiliations
Review

Stapled peptides as potential inhibitors of SARS-CoV-2 binding to the hACE2 receptor

Susan Tzotzos. J Pept Sci. 2022 Sep.

Abstract

Stapled peptides are synthetic peptidomimetics of bioactive sites in folded proteins which carry chemical links, introduced during peptide synthesis, designed to retain the secondary structure in the native protein molecule. Stapled peptides have been investigated as potential modulators of protein-protein interactions for over two decades. The potential use of stapled peptides as inhibitors of viral entry, and therefore as antiviral therapeutics, has been established for several important viruses causing disease in humans, such as the human immunodeficiency virus type 1 (HIV-1), respiratory syncytial virus (RSV), and Middle East Respiratory Syndrome (MERS) coronavirus. Several independent research initiatives have investigated the inhibitory effect of stapled peptides on binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, to its receptor, angiotensin-converting-enzyme 2 (ACE2). These stapled peptides, which mimic Helix 1 of the human ACE2 receptor, have demonstrated mixed ability to prevent infection with SARS-CoV-2 in cell-based studies.

Keywords: COVID-19; SARS-CoV-2; hACE2; inhibitor; peptide; stapling; therapeutic.

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Figures

FIGURE 1
FIGURE 1
Simplified schematic to illustrate how severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) enters host cells (adapted with permission from Scudellari M, “How the coronavirus infects cells—And why Delta is so dangerous”, Nature, 2021, Springer Nature B.V. [ 23 ])
FIGURE 2
FIGURE 2
Cryo‐EM structures of the full‐length severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) S protein carrying G614. Three structures of the G614 S trimer representing a closed, three “receptor‐binding domain (RBD) down” conformation, an RBD intermediate conformation and a one “RBDup” conformation modeled on the basis of corresponding cryo‐EM density maps at 3.1‐ and 3.5‐Å resolution (adapted with permission from Zhang J, “Structural impact on SARS‐CoV‐2 spike protein by D614G substitution”, Science, 2021, John Wiley & Sons[ 26 ])
FIGURE 3
FIGURE 3
X‐ray structure (PDB ID:6m0j) showing binding of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) receptor‐binding domain (RBD) (purple), including the interacting receptor binding motif (RBM) (yellow) with the hACE2 receptor (blue). Detailed interactions of helix 1 of hACE2 (orange) with the SARS‐CoV‐2 RBD are magnified in the illustration on the right.[ 28 ] Residues in hACE2 colored orange, in the SARS‐CoV‐2 RBD, black. Molecular graphics performed with UCSF Chimera, version 1.14[ 29 ]
FIGURE 4
FIGURE 4
Stapled peptides based on Helix 1 of hACE2 (UniProt: Q9BYF1, ACE2_HUMAN). Peptides NYBSP‐4[ 2 ] and hACE221‐55A36K‐F40E[ 35 ] inhibited entry of SARS‐CoV‐2 in cell‐based assays. Peptide Modification 15[ 36 ] showed binding to SARS‐CoV‐2 RBD in silico with similar docking scores to NYBSP‐4. Peptide 8[ 37 ] did not inhibit entry of SARS‐CoV‐2 in cell‐based assays. Be, lactam bridge formed by Lys‐Glu side chain bonding; Bd, lactam bridge formed by Lys‐Asp side chain bonding; J, double lactam bridge formed by Glu‐Orn‐Glu bonding; X, S‐2‐(4‐pentenyl)alanine; Z, R‐2‐(7‐octenyl)alanine. Residues and chemical groups shown in red differ from wild‐type sequence. Images of staples produced using UCSF Chimera, version 1.14[ 29 ] and ChemSketch
FIGURE 5
FIGURE 5
Graphic to show different stapling positions in peptides NYBSP‐4,[ 2 ] hACE221‐55A36K‐F40E,[ 35 ] and Peptide 8,[ 37 ] modeled in the context of the crystal structure of the SARS‐CoV‐2 spike receptor‐binding domain (RBD) bound to the ACE2 receptor (PDB ID:6m0j).[ 28 ] Residues important for binding labeled in peptides, K31 (orange), and in SARS‐CoV‐2 spike RBD, Q493 and T500 (black). Coloring as in Figure 3. Molecular graphics performed with UCSF Chimera, version 1.14[ 29 ]
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