An In Silico Design of Peptides Targeting the S1/S2 Cleavage Site of the SARS-CoV-2 Spike Protein
SARS-CoV-2, responsible for the COVID-19 pandemic, invades host cells via its spike protein, which includes critical binding regions, such as the receptor-binding domain (RBD), the S1/S2 cleavage site, the S2 cleavage site, and heptad-repeat (HR) sections. Peptides targeting the RBD and HR1 inhibit...
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| Format: | Article |
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MDPI AG
2023-09-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/15/9/1930 |
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| author | Chian Ho Wan Fahmi Wan Mohamad Nazarie Ping-Chin Lee |
| author_facet | Chian Ho Wan Fahmi Wan Mohamad Nazarie Ping-Chin Lee |
| author_sort | Chian Ho |
| collection | DOAJ |
| description | SARS-CoV-2, responsible for the COVID-19 pandemic, invades host cells via its spike protein, which includes critical binding regions, such as the receptor-binding domain (RBD), the S1/S2 cleavage site, the S2 cleavage site, and heptad-repeat (HR) sections. Peptides targeting the RBD and HR1 inhibit binding to host ACE2 receptors and the formation of the fusion core. Other peptides target proteases, such as TMPRSS2 and cathepsin L, to prevent the cleavage of the S protein. However, research has largely ignored peptides targeting the S1/S2 cleavage site. In this study, bioinformatics was used to investigate the binding of the S1/S2 cleavage site to host proteases, including furin, trypsin, TMPRSS2, matriptase, cathepsin B, and cathepsin L. Peptides targeting the S1/S2 site were designed by identifying binding residues. Peptides were docked to the S1/S2 site using HADDOCK (High-Ambiguity-Driven protein–protein DOCKing). Nine peptides with the lowest HADDOCK scores and strong binding affinities were selected, which was followed by molecular dynamics simulations (MDSs) for further investigation. Among these peptides, BR582 and BR599 stand out. They exhibited relatively high interaction energies with the S protein at −1004.769 ± 21.2 kJ/mol and −1040.334 ± 24.1 kJ/mol, respectively. It is noteworthy that the binding of these peptides to the S protein remained stable during the MDSs. In conclusion, this research highlights the potential of peptides targeting the S1/S2 cleavage site as a means to prevent SARS-CoV-2 from entering cells, and contributes to the development of therapeutic interventions against COVID-19. |
| first_indexed | 2024-03-10T21:52:03Z |
| format | Article |
| id | doaj.art-fb536ebbac3d4e5ca00c162c2c8dda09 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T21:52:03Z |
| publishDate | 2023-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-fb536ebbac3d4e5ca00c162c2c8dda092023-11-19T13:23:43ZengMDPI AGViruses1999-49152023-09-01159193010.3390/v15091930An In Silico Design of Peptides Targeting the S1/S2 Cleavage Site of the SARS-CoV-2 Spike ProteinChian Ho0Wan Fahmi Wan Mohamad Nazarie1Ping-Chin Lee2Faculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, MalaysiaFaculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, MalaysiaFaculty of Science and Natural Resources, Universiti Malaysia Sabah, Kota Kinabalu 88400, Sabah, MalaysiaSARS-CoV-2, responsible for the COVID-19 pandemic, invades host cells via its spike protein, which includes critical binding regions, such as the receptor-binding domain (RBD), the S1/S2 cleavage site, the S2 cleavage site, and heptad-repeat (HR) sections. Peptides targeting the RBD and HR1 inhibit binding to host ACE2 receptors and the formation of the fusion core. Other peptides target proteases, such as TMPRSS2 and cathepsin L, to prevent the cleavage of the S protein. However, research has largely ignored peptides targeting the S1/S2 cleavage site. In this study, bioinformatics was used to investigate the binding of the S1/S2 cleavage site to host proteases, including furin, trypsin, TMPRSS2, matriptase, cathepsin B, and cathepsin L. Peptides targeting the S1/S2 site were designed by identifying binding residues. Peptides were docked to the S1/S2 site using HADDOCK (High-Ambiguity-Driven protein–protein DOCKing). Nine peptides with the lowest HADDOCK scores and strong binding affinities were selected, which was followed by molecular dynamics simulations (MDSs) for further investigation. Among these peptides, BR582 and BR599 stand out. They exhibited relatively high interaction energies with the S protein at −1004.769 ± 21.2 kJ/mol and −1040.334 ± 24.1 kJ/mol, respectively. It is noteworthy that the binding of these peptides to the S protein remained stable during the MDSs. In conclusion, this research highlights the potential of peptides targeting the S1/S2 cleavage site as a means to prevent SARS-CoV-2 from entering cells, and contributes to the development of therapeutic interventions against COVID-19.https://www.mdpi.com/1999-4915/15/9/1930SARS-CoV-2S1/S2 cleavage sitepeptidesHADDOCKmolecular dynamics simulation |
| spellingShingle | Chian Ho Wan Fahmi Wan Mohamad Nazarie Ping-Chin Lee An In Silico Design of Peptides Targeting the S1/S2 Cleavage Site of the SARS-CoV-2 Spike Protein Viruses SARS-CoV-2 S1/S2 cleavage site peptides HADDOCK molecular dynamics simulation |
| title | An In Silico Design of Peptides Targeting the S1/S2 Cleavage Site of the SARS-CoV-2 Spike Protein |
| title_full | An In Silico Design of Peptides Targeting the S1/S2 Cleavage Site of the SARS-CoV-2 Spike Protein |
| title_fullStr | An In Silico Design of Peptides Targeting the S1/S2 Cleavage Site of the SARS-CoV-2 Spike Protein |
| title_full_unstemmed | An In Silico Design of Peptides Targeting the S1/S2 Cleavage Site of the SARS-CoV-2 Spike Protein |
| title_short | An In Silico Design of Peptides Targeting the S1/S2 Cleavage Site of the SARS-CoV-2 Spike Protein |
| title_sort | in silico design of peptides targeting the s1 s2 cleavage site of the sars cov 2 spike protein |
| topic | SARS-CoV-2 S1/S2 cleavage site peptides HADDOCK molecular dynamics simulation |
| url | https://www.mdpi.com/1999-4915/15/9/1930 |
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