Structure–Activity‐Related Analysis of ACE Inhibitory Peptides Against Furin: A Dual‐Action Therapeutic Approach Against SARS‐CoV‐2

The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which is responsible for the COVID‐19 pandemic, enters host cells by binding its spike protein to the angiotensin‐converting enzyme 2 (ACE) receptor on the surface of lung endothelial cells. ACE inhibitors, which were used to manage hypertension, have shown potential to interfere with this viral entry mechanism. This study investigates the dual inhibitory potential of ACE inhibitory peptides against furin, an essential enzyme for the activation of the SARS‐CoV‐2 spike protein. A molecular docking study was performed to identify key interacting amino acid residues at the N‐ and C‐termini that stabilize peptide–furin interactions. Key residues, including ARG, LYS, ALA, and VAL, along with the hydrophobic amino acids PRO, GLY, and LEU, play significant roles in stabilizing these interactions via hydrophobic forces. These residues enhance peptide–enzyme affinity by contributing structural rigidity and flexibility, optimizing binding orientation. The analysis revealed that most ACE inhibitory peptides engage in noncompetitive inhibition by binding to an allosteric site on furin, composed of key residues, such as GLU271, GLY307, SER311, TYR313, LYS449, GLN488, ARG490, ASP530, and ALA532. In vitro and in vivo studies are necessary to further evaluate the therapeutic safety and efficacy of these peptides, paving the way for innovative treatment strategies against COVID‐19.