The Renin–Angiotensin System Modulates SARS-CoV-2 Entry via ACE2 Receptor
The renin–angiotensin system (RAS) plays a central role in cardiovascular regulation and has gained prominence in the pathogenesis of Coronavirus Disease 2019 (COVID-19) due to the critical function of angiotensin-converting enzyme 2 (ACE2) as the entry receptor for severe acute respiratory syndrome...
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2025-07-01
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| author | Sophia Gagliardi Tristan Hotchkin Hasset Tibebe Grace Hillmer Dacia Marquez Coco Izumi Jason Chang Alexander Diggs Jiro Ezaki Yuichiro J. Suzuki Taisuke Izumi |
| author_facet | Sophia Gagliardi Tristan Hotchkin Hasset Tibebe Grace Hillmer Dacia Marquez Coco Izumi Jason Chang Alexander Diggs Jiro Ezaki Yuichiro J. Suzuki Taisuke Izumi |
| author_sort | Sophia Gagliardi |
| collection | DOAJ |
| description | The renin–angiotensin system (RAS) plays a central role in cardiovascular regulation and has gained prominence in the pathogenesis of Coronavirus Disease 2019 (COVID-19) due to the critical function of angiotensin-converting enzyme 2 (ACE2) as the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin IV, but not angiotensin II, has recently been reported to enhance the binding between the viral spike protein and ACE2. To investigate the virological significance of this effect, we developed a single-round infection assay using SARS-CoV-2 viral-like particles expressing the spike protein. Our results demonstrate that while angiotensin II does not affect viral infectivity across concentrations ranging from 40 nM to 400 nM, angiotensin IV enhances viral entry at a low concentration but exhibits dose-dependent inhibition at higher concentrations. These findings highlight the unique dual role of angiotensin IV in modulating SARS-CoV-2 entry. In silico molecular docking simulations indicate that angiotensin IV was predicted to associate with the S1 domain near the receptor-binding domain in the open spike conformation. Given that reported plasma concentrations of angiotensin IV range widely from 17 pM to 81 nM, these levels may be sufficient to promote, rather than inhibit, SARS-CoV-2 infection. This study identifies a novel link between RAS-derived peptides and SARS-CoV-2 infectivity, offering new insights into COVID-19 pathophysiology and informing potential therapeutic strategies. |
| format | Article |
| id | doaj-art-780f0aa8e29b4e559267afc3e07e24ca |
| institution | DOAJ |
| issn | 1999-4915 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj-art-780f0aa8e29b4e559267afc3e07e24ca2025-08-20T02:47:14ZengMDPI AGViruses1999-49152025-07-01177101410.3390/v17071014The Renin–Angiotensin System Modulates SARS-CoV-2 Entry via ACE2 ReceptorSophia Gagliardi0Tristan Hotchkin1Hasset Tibebe2Grace Hillmer3Dacia Marquez4Coco Izumi5Jason Chang6Alexander Diggs7Jiro Ezaki8Yuichiro J. Suzuki9Taisuke Izumi10Department of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USADepartment of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC 20007, USADepartment of Biology, College of Arts & Sciences, American University, Washington, DC 20016, USAThe renin–angiotensin system (RAS) plays a central role in cardiovascular regulation and has gained prominence in the pathogenesis of Coronavirus Disease 2019 (COVID-19) due to the critical function of angiotensin-converting enzyme 2 (ACE2) as the entry receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Angiotensin IV, but not angiotensin II, has recently been reported to enhance the binding between the viral spike protein and ACE2. To investigate the virological significance of this effect, we developed a single-round infection assay using SARS-CoV-2 viral-like particles expressing the spike protein. Our results demonstrate that while angiotensin II does not affect viral infectivity across concentrations ranging from 40 nM to 400 nM, angiotensin IV enhances viral entry at a low concentration but exhibits dose-dependent inhibition at higher concentrations. These findings highlight the unique dual role of angiotensin IV in modulating SARS-CoV-2 entry. In silico molecular docking simulations indicate that angiotensin IV was predicted to associate with the S1 domain near the receptor-binding domain in the open spike conformation. Given that reported plasma concentrations of angiotensin IV range widely from 17 pM to 81 nM, these levels may be sufficient to promote, rather than inhibit, SARS-CoV-2 infection. This study identifies a novel link between RAS-derived peptides and SARS-CoV-2 infectivity, offering new insights into COVID-19 pathophysiology and informing potential therapeutic strategies.https://www.mdpi.com/1999-4915/17/7/1014angiotensinrenin–angiotensin systemangiotensin-converting enzyme 2severe acute respiratory syndrome coronavirus 2spike proteinviral-like particle |
| spellingShingle | Sophia Gagliardi Tristan Hotchkin Hasset Tibebe Grace Hillmer Dacia Marquez Coco Izumi Jason Chang Alexander Diggs Jiro Ezaki Yuichiro J. Suzuki Taisuke Izumi The Renin–Angiotensin System Modulates SARS-CoV-2 Entry via ACE2 Receptor Viruses angiotensin renin–angiotensin system angiotensin-converting enzyme 2 severe acute respiratory syndrome coronavirus 2 spike protein viral-like particle |
| title | The Renin–Angiotensin System Modulates SARS-CoV-2 Entry via ACE2 Receptor |
| title_full | The Renin–Angiotensin System Modulates SARS-CoV-2 Entry via ACE2 Receptor |
| title_fullStr | The Renin–Angiotensin System Modulates SARS-CoV-2 Entry via ACE2 Receptor |
| title_full_unstemmed | The Renin–Angiotensin System Modulates SARS-CoV-2 Entry via ACE2 Receptor |
| title_short | The Renin–Angiotensin System Modulates SARS-CoV-2 Entry via ACE2 Receptor |
| title_sort | renin angiotensin system modulates sars cov 2 entry via ace2 receptor |
| topic | angiotensin renin–angiotensin system angiotensin-converting enzyme 2 severe acute respiratory syndrome coronavirus 2 spike protein viral-like particle |
| url | https://www.mdpi.com/1999-4915/17/7/1014 |
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