Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals,...
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2024-11-01
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| author | Harry Ridgway Vasso Apostolopoulos Graham J. Moore Laura Kate Gadanec Anthony Zulli Jordan Swiderski Sotirios Tsiodras Konstantinos Kelaidonis Christos T. Chasapis John M. Matsoukas |
| author_facet | Harry Ridgway Vasso Apostolopoulos Graham J. Moore Laura Kate Gadanec Anthony Zulli Jordan Swiderski Sotirios Tsiodras Konstantinos Kelaidonis Christos T. Chasapis John M. Matsoukas |
| author_sort | Harry Ridgway |
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| description | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn<sup>2+</sup>) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2′, suggesting interference with SARS-CoV-2’s spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies. |
| format | Article |
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| institution | OA Journals |
| issn | 1999-4915 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
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| series | Viruses |
| spelling | doaj-art-effde1e4cc9546c1a3d7ad1ab0fc40872025-08-20T02:04:43ZengMDPI AGViruses1999-49152024-11-011611177610.3390/v16111776Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial VirusesHarry Ridgway0Vasso Apostolopoulos1Graham J. Moore2Laura Kate Gadanec3Anthony Zulli4Jordan Swiderski5Sotirios Tsiodras6Konstantinos Kelaidonis7Christos T. Chasapis8John M. Matsoukas9Institute for Sustainable Industries and Liveable Cities, Victoria University, Melbourne, VIC 8001, AustraliaSchool of Health and Biomedical Sciences, RMIT University, Bundoora, Melbourne, VIC 3083, AustraliaPepmetics Inc., 772 Murphy Place, Victoria, BC V6Y 3H4, CanadaInstitute for Health and Sport, Immunology and Translational Research Group, Victoria University, Werribee, Melbourne, VIC 3030, AustraliaInstitute for Health and Sport, Immunology and Translational Research Group, Victoria University, Werribee, Melbourne, VIC 3030, AustraliaInstitute for Health and Sport, Immunology and Translational Research Group, Victoria University, Werribee, Melbourne, VIC 3030, Australia4th Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, GreeceNewDrug PC, Patras Science Park, 26504 Patras, GreeceInstitute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, GreeceInstitute for Health and Sport, Immunology and Translational Research Group, Victoria University, Werribee, Melbourne, VIC 3030, AustraliaSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza, and respiratory syncytial virus (RSV) are significant global health threats. The need for low-cost, easily synthesized oral drugs for rapid deployment during outbreaks is crucial. Broad-spectrum therapeutics, or pan-antivirals, are designed to target multiple viral pathogens simultaneously by focusing on shared molecular features, such as common metal cofactors or conserved residues in viral catalytic domains. This study introduces a new generation of potent sartans, known as bisartans, engineered in our laboratories with negative charges from carboxylate or tetrazolate groups. These anionic tetrazoles interact strongly with cationic arginine residues or metal cations (e.g., Zn<sup>2+</sup>) within viral and host target sites, including the SARS-CoV-2 ACE2 receptor, influenza H1N1 neuraminidases, and the RSV fusion protein. Using virtual ligand docking and molecular dynamics, we investigated how bisartans and their analogs bind to these viral receptors, potentially blocking infection through a pan-antiviral mechanism. Bisartan, ACC519TT, demonstrated stable and high-affinity docking to key catalytic domains of the SARS-CoV-2 NSP3, H1N1 neuraminidase, and RSV fusion protein, outperforming FDA-approved drugs like Paxlovid and oseltamivir. It also showed strong binding to the arginine-rich furin cleavage sites S1/S2 and S2′, suggesting interference with SARS-CoV-2’s spike protein cleavage. The results highlight the potential of tetrazole-based bisartans as promising candidates for developing broad-spectrum antiviral therapies.https://www.mdpi.com/1999-4915/16/11/1776arginine blockersbisartansbenzimidazole sartanscoronavirus 2019influenzapan-antivirals |
| spellingShingle | Harry Ridgway Vasso Apostolopoulos Graham J. Moore Laura Kate Gadanec Anthony Zulli Jordan Swiderski Sotirios Tsiodras Konstantinos Kelaidonis Christos T. Chasapis John M. Matsoukas Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses Viruses arginine blockers bisartans benzimidazole sartans coronavirus 2019 influenza pan-antivirals |
| title | Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses |
| title_full | Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses |
| title_fullStr | Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses |
| title_full_unstemmed | Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses |
| title_short | Computational Evidence for Bisartan Arginine Blockers as Next-Generation Pan-Antiviral Therapeutics Targeting SARS-CoV-2, Influenza, and Respiratory Syncytial Viruses |
| title_sort | computational evidence for bisartan arginine blockers as next generation pan antiviral therapeutics targeting sars cov 2 influenza and respiratory syncytial viruses |
| topic | arginine blockers bisartans benzimidazole sartans coronavirus 2019 influenza pan-antivirals |
| url | https://www.mdpi.com/1999-4915/16/11/1776 |
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