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Targeting Matrix Metalloproteinase-1, Matrix Metalloproteinase-7, and Serine Protease Inhibitor E1: Implications in
Vibha Mishra1, Shivangi Agrawal1, Divya Malik1
1Bioinformatics Department, MMV, Institute of Science, Banaras Hindu University, India.
Background:
SARS-CoV-2 disrupts lung vascular endothelial integrity, contributing to severe COVID-19 complications. However, the molecular mechanisms driving endothelial dysfunction remain underexplored, and targeted therapeutic strategies are lacking.
Objective:
This study investigates Naringenin-7-O-glucoside (N7G) as a multi-target therapeutic candidate for modulating vascular integrity and immune response by inhibiting MMP1, MMP7, and SERPINE1-key regulators of extracellular matrix (ECM) remodeling and inflammation.
Methods & Results:
RNA-seq analysis of COVID-19 lung tissues identified 17 upregulated N7G targets, including MMP1, MMP7, and SERPINE1, with the latter exhibiting the highest expression. PPI network analysis linked these targets to ECM degradation, IL-17, HIF-1, and AGE-RAGE signaling pathways, and endothelial dysfunction. Disease enrichment associated these genes with idiopathic pulmonary fibrosis and asthma. Molecular docking, 200 ns MD simulations (triplicate), and MMGBSA calculations confirmed N7G's stable binding affinity to MMP1, MMP7, and SERPINE1. Immune profiling revealed increased neutrophils and activated CD4+ T cells, alongside reduced mast cells, NK cells, and naïve B cells, indicating immune dysregulation. Correlation analysis linked MMP1, MMP7, and SERPINE1 to distinct immune cell populations, supporting N7G's immunomodulatory role.
Conclusion:
These findings suggest that N7G exhibits multi-target therapeutic potential by modulating vascular integrity, ECM remodeling, and immune dysregulation, positioning it as a promising candidate for mitigating COVID-19-associated endothelial dysfunction.
Insights
Naringenin-7-O-glucoside (N7G) shows potential for treating COVID-19 by stabilizing lung vascular integrity and modulating immune responses. This natural compound targets key enzymes involved in inflammation and tissue remodeling, offering a promising therapeutic avenue.
Area of Science:
- Molecular Biology
- Immunology
- Pharmacology
Background:
- SARS-CoV-2 infection severely impacts lung vascular endothelial integrity, leading to critical COVID-19 complications.
- The precise molecular mechanisms behind endothelial dysfunction and effective therapeutic strategies remain largely unaddressed.
Purpose of the Study:
- To investigate Naringenin-7-O-glucoside (N7G) as a potential multi-target therapeutic agent.
- To evaluate N7G's ability to modulate vascular integrity and immune responses by inhibiting MMP1, MMP7, and SERPINE1.
Main Methods:
- RNA-sequencing of COVID-19 lung tissues to identify N7G targets.
- Protein-protein interaction (PPI) network and disease enrichment analyses.
- Molecular docking, molecular dynamics (MD) simulations, and MMGBSA calculations.
- Immune profiling and correlation analysis.
Main Results:
- N7G targets include MMP1, MMP7, and SERPINE1, linked to ECM degradation and inflammatory pathways.
- N7G demonstrated stable binding affinity to MMP1, MMP7, and SERPINE1.
- Significant alterations in immune cell populations (neutrophils, CD4+ T cells, mast cells, NK cells, B cells) were observed, indicating immune dysregulation.
Conclusions:
- Naringenin-7-O-glucoside (N7G) exhibits multi-target therapeutic potential for COVID-19.
- N7G may mitigate endothelial dysfunction by modulating vascular integrity, ECM remodeling, and immune responses.
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