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J Med Virol
. 2026 Jul;98(7):e71060.
doi: 10.1002/jmv.71060.
ACE2- and HR2-Mimetic Peptides Inhibit Replication of Two SARS-CoV-2 Variants
Melvin E Zúñiga-Hernández 1 , Karen L Reyes-Barrera 1 2 , Sergio N Hidalgo-Figueroa 3 , Edgar D Páez-Pérez 1 4 , Clara I Espitia Pinzón 2 , Ángel G Alpuche-Solís 1
Affiliations
Several therapeutic approaches to inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focus on blocking the virus's entry mechanism. This can be blocked in two ways: by interacting with the receptor-binding domain (RBD) of the spike protein and human angiotensin-converting enzyme 2 (ACE2), and by blocking viral-cellular membrane fusion. Here, we designed mimetic peptides based on ACE2 and the region of the viral spike stem. Through in silico molecular docking, we select the peptides with the highest binding energy. The peptides Nat (P-Nat) and 3 (P-3) inhibited RBD-ACE2 interaction in a surrogate ELISA assay by 54% and 58.77%, respectively. On the other hand, P-Nat and P-3 inhibited SARS-CoV-2 in VeroE6 cells, showing 50% inhibitory concentration (IC50) values of 6.28 and 12.79 μM against Wuhan and 6.26 and 7.27 μM against Omicron, respectively. Meanwhile, the stem mimetic peptide (P-K2) showed an IC50 of 29.17 μM against Omicron. Therefore, P-Nat and P-3 are good candidates to inhibit both variants of SARS-CoV-2, while P-K2 shows inhibitory activity against the Omicron variant. We propose that these peptides could be used as prophylactic agents prior to viral infection, as they are specifically designed to block viral entry into host cells.
Keywords: ACE2‐mimetic peptides; HR2‐mimetic peptides; SARS‐CoV‐2 variants; binding assay; blocking entry; microneutralization.
. 2026 Jul;98(7):e71060.
doi: 10.1002/jmv.71060.
ACE2- and HR2-Mimetic Peptides Inhibit Replication of Two SARS-CoV-2 Variants
Melvin E Zúñiga-Hernández 1 , Karen L Reyes-Barrera 1 2 , Sergio N Hidalgo-Figueroa 3 , Edgar D Páez-Pérez 1 4 , Clara I Espitia Pinzón 2 , Ángel G Alpuche-Solís 1
Affiliations
- PMID: 42473348
- DOI: 10.1002/jmv.71060
Several therapeutic approaches to inhibiting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focus on blocking the virus's entry mechanism. This can be blocked in two ways: by interacting with the receptor-binding domain (RBD) of the spike protein and human angiotensin-converting enzyme 2 (ACE2), and by blocking viral-cellular membrane fusion. Here, we designed mimetic peptides based on ACE2 and the region of the viral spike stem. Through in silico molecular docking, we select the peptides with the highest binding energy. The peptides Nat (P-Nat) and 3 (P-3) inhibited RBD-ACE2 interaction in a surrogate ELISA assay by 54% and 58.77%, respectively. On the other hand, P-Nat and P-3 inhibited SARS-CoV-2 in VeroE6 cells, showing 50% inhibitory concentration (IC50) values of 6.28 and 12.79 μM against Wuhan and 6.26 and 7.27 μM against Omicron, respectively. Meanwhile, the stem mimetic peptide (P-K2) showed an IC50 of 29.17 μM against Omicron. Therefore, P-Nat and P-3 are good candidates to inhibit both variants of SARS-CoV-2, while P-K2 shows inhibitory activity against the Omicron variant. We propose that these peptides could be used as prophylactic agents prior to viral infection, as they are specifically designed to block viral entry into host cells.
Keywords: ACE2‐mimetic peptides; HR2‐mimetic peptides; SARS‐CoV‐2 variants; binding assay; blocking entry; microneutralization.