Naringenin-7-O-glucoside：针对 COVID-19 肺部病理学和免疫调节的 SERPINE1、MMP7 和 MMP1,ChemRxiv

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Naringenin-7-O-glucoside：针对 COVID-19 肺部病理学和免疫调节的 SERPINE1、MMP7 和 MMP1
ChemRxiv Pub Date : 2023-12-28 , DOI: 10.26434/chemrxiv-2023-4bddw
Vibha Mishra ₁ , Shivangi Agrawal ₁ , Divya Malik ₁ , Ekta Pathak ₂ , Rajeev Mishra ₁

Affiliation

由 SARS-CoV-2 病毒引起的 COVID-19 大流行已成为一场决定性的全球健康危机，其特点是严重的呼吸困难和高死亡率。寻找针对这种高度变异病毒的有效治疗方法一直是一项重大挑战。在这里，我们探讨了柚皮素-7-O-葡萄糖苷 (N7G)（一种生物活性黄酮苷）在 COVID-19 背景下的治疗潜力。以其广泛的药理作用而闻名，包括抗病毒、抗菌、抗疟和抗癌特性，利用 EBI 表达图谱中的基因表达数据，我们分析了已故 COVID-19 患者和健康个体的肺部样本，以了解 N7G 的分子机制和潜力治疗目标。我们的富集分析揭示了 N7G 靶标与免疫反应和细胞信号转导中至关重要的生物功能和途径之间的显着关联。我们强调了 HIF-1、AGE-RAGE 和 IL-17 等通路在 COVID-19 等疾病发病机制中的重要性。抑制 HIF-1 通路可以减轻肺部炎症，同时针对氧化应激和炎症中的关键角色 AGE-RAGE 通路，成为一种有前途的策略。调节与感染期间细胞因子风暴有关的 IL-17 途径也可能有效。此外，以其抗炎和抗纤维化特性而闻名的松弛素信号通路被确定为治疗 COVID-19 后综合征或长期 COVID 的潜在靶点。我们优先考虑 SERPINE1、MMP7 和 MMP1 作为关键治疗靶点。COVID-19 患者中 SERPINE1 水平升高与早期死亡风险有关，并参与血小板脱粒和纤溶损伤等过程，导致血小板减少。MMP1 和 MMP7 是基质金属蛋白酶家族的一部分，在组织稳态中发挥着至关重要的作用，并已被确定为 COVID-19 的生物标志物和潜在治疗靶点，与肺水肿和严重炎症反应有关。我们的分子对接和 MD 模拟研究一式三份进行超过 200 ns，证明了 N7G 与 MMP7 和 SERPINE1 形成稳定的复合物。与其他 MMP7 抑制剂类似，N7G 始终占据 MMP7 的锌结合催化位点，并与 SERPINE1 的抑制剂位点紧密结合，表明存在很强的相互作用。MMGBSA 分析证实了这些复合物的稳定性，表明 N7G 对这些靶标具有有效的抑制潜力。尽管 N7G 与 MMP1 短暂形成复合物，但其在 COVID-19 发病机制中，特别是在炎症中的作用不可忽视。MMP1 水平升高与 COVID-19 患者炎症反应增加相关，这强调了其作为治疗靶点的重要性。总之，我们的研究确定 MMP7、MMP1 和 SERPINE1 是 N7G 对抗 COVID-19 的关键免疫相关靶点。结果使 N7G 成为治疗 COVID-19 引起的肺部炎症和长期 COVID 的潜在新型抑制剂。然而，这些初步发现需要进一步验证。这项研究有助于了解天然化合物在病毒感染治疗中的作用，为探索 N7G 等黄酮类化合物对抗 SARS-CoV-2 和其他病毒开辟了途径。它强调了包括天然物质在内的多种治疗策略在应对 COVID-19 全球挑战方面的重要性。

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Naringenin-7-O-glucoside: Targeting SERPINE1, MMP7, and MMP1 for COVID-19 Lung Pathology and Immune Modulation

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been a defining global health crisis, marked by severe respiratory distress and high mortality rates. The search for effective treatments against this highly mutable virus has been a significant challenge. Here, we explored the therapeutic potential of Naringenin-7-O-glucoside (N7G), a bioactive flavone glycoside, in the context of COVID-19. Known for its wide-ranging pharmacological effects, including antiviral, antibacterial, antimalarial, and anticancer properties, Utilizing gene expression data from the EBI Expression Atlas, we analyzed lung samples from deceased COVID-19 patients and healthy individuals to understand N7G’s molecular mechanisms and potential therapeutic targets. Our enrichment analysis revealed a significant association of N7G targets with biological functions and pathways crucial in immune responses and cellular signaling. We highlighted the importance of pathways such as HIF-1, AGE-RAGE, and IL-17 in the pathogenesis of diseases like COVID-19. Suppressing the HIF-1 pathway could mitigate lung inflammation, while targeting the AGE-RAGE pathway, a key player in oxidative stress and inflammation, emerges as a promising strategy. Modulating the IL-17 pathway, implicated in cytokine storms during infection, could also be effective. Furthermore, the relaxin signaling pathway, known for its anti-inflammatory and anti-fibrotic properties, was identified as a potential target for post-COVID-19 syndrome or long-haul COVID. We prioritized SERPINE1, MMP7, and MMP1 as key therapeutic targets. Elevated SERPINE1 levels in COVID-19 patients have been linked to early mortality risk and are involved in processes like platelet degranulation and fibrinolysis impairment, contributing to thrombocytopenia. MMP1 and MMP7, part of the matrix metalloproteinases family, play crucial roles in tissue homeostasis and have been identified as biomarkers and potential therapeutic targets in COVID-19, linked to pulmonary edema and severe inflammatory responses. Our molecular docking and MD simulation studies, conducted over 200 ns in triplicates, demonstrated stable complex formation of N7G with MMP7 and SERPINE1. N7G consistently occupied the zinc binding catalytic site of MMP7, similar to other MMP7 inhibitors, and tightly bound to the inhibitor site of SERPINE1, indicating strong interactions. The MMGBSA analysis confirmed the stability of these complexes, suggesting the effective inhibitory potential of N7G against these targets. Although N7G showed transient complex formation with MMP1, its role in COVID-19 pathogenesis, particularly in inflammation, cannot be ignored. Elevated MMP1 levels have been associated with increased inflammatory responses in COVID-19 patients, underscoring its importance as a therapeutic target. In conclusion, our study identifies MMP7, MMP1, and SERPINE1 as critical immune-related targets of N7G in combating COVID-19. The results position N7G as a potential novel inhibitor for treating COVID-19-induced lung inflammation and long-haul COVID. However, these initial findings require further validation. This study contributes to the understanding of natural compounds in viral infection treatment, opening pathways for exploring flavonoids like N7G against SARS-CoV-2 and other viruses. It underscores the importance of diverse therapeutic strategies, including natural substances, in combating the global challenge of COVID-19.

更新日期：2023-12-28

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