Naringenin-7-O-glucoside: Targeting SERPINE1, MMP7, and MMP1 for COVID-19 Lung Pathology and Immune Modulation
Authors: Mishra Vibha , Agrawal Shivangi , Malik Divya , Pathak Ekta , Mishra Rajeev 
Published: December 2023

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.