Gagliardi Sophia, Hotchkin Tristan, Tibebe Hasset, Hillmer Grace, Marquez Dacia, Izumi Coco, Chang Jason, Diggs Alexander, Ezaki Jiro, Suzuki Yuichiro J J, Izumi Taisuke
bioRxiv. 2025 Jun 25:2025.06.25.661409. doi: 10.1101/2025.06.25.661409.
The RAS plays a central role in cardiovascular regulation and has gained prominence in the pathogenesis of COVID-19 due to the critical function of ACE2 as the entry receptor for 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.
肾素-血管紧张素系统（RAS）在心血管调节中起核心作用，由于血管紧张素转换酶2（ACE2）作为严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的进入受体的关键功能，其在2019冠状病毒病（COVID-19）发病机制中也备受关注。最近有报道称，血管紧张素IV而非血管紧张素II可增强病毒刺突蛋白与ACE2之间的结合。为了研究这种作用的病毒学意义，我们利用表达刺突蛋白的SARS-CoV-2病毒样颗粒开发了一种单轮感染试验。我们的结果表明，虽然血管紧张素II在40 nM至400 nM的浓度范围内不影响病毒感染性，但血管紧张素IV在低浓度时增强病毒进入，但在较高浓度时表现出剂量依赖性抑制作用。这些发现突出了血管紧张素IV在调节SARS-CoV-2进入方面独特的双重作用。计算机分子对接模拟表明，血管紧张素IV预计会与开放刺突构象中受体结合域附近的S1结构域结合。鉴于报道的血管紧张素IV血浆浓度范围广泛，从17 pM到81 nM，这些水平可能足以促进而非抑制SARS-CoV-2感染。本研究确定了RAS衍生肽与SARS-CoV-2感染性之间的新联系，为COVID-19病理生理学提供了新见解，并为潜在治疗策略提供了信息。
