Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis
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Suvojit Hazra1, Alok Ghosh Chaudhuri2, Basant K Tiwary3
1CPEPA-UGC Centre for "Electro-physiological and Neuro-imaging studies including Mathematical Modelling", University of Calcutta, Kolkata, West Bengal, India; Department of Physiology, University of Calcutta, Kolkata, West Bengal, India.
Aims:
The molecular pathogenesis of COVID-19 is similar to other coronavirus (CoV) infections viz. severe acute respiratory syndrome (SARS) in human. Due to scarcity of the suitable treatment strategy, the present study was undertaken to explore host protein(s) targeted by potent repurposed drug(s) in COVID-19.
Materials And Methods:
The differentially expressed genes (DEGs) were identified from microarray data repository of SARS-CoV patient blood. The repurposed drugs for COVID-19 were selected from available literature. Using DEGs and drugs, the protein-protein interaction (PPI) and chemo-protein interaction (CPI) networks were constructed and combined to develop an interactome model of PPI-CPI network. The top-ranked sub-network with its hub-bottleneck nodes were evaluated with their functional annotations.
Key Findings:
A total of 120 DEGs and 65 drugs were identified. The PPI-CPI network (118 nodes and 293 edges) exhibited a top-ranked sub-network (35 nodes and 174 connectivities) with 12 hub-bottleneck nodes having two drugs chloroquine and melatonin in association with 10 proteins corresponding to six upregulated and four downregulated genes. Two drugs interacted directly with the hub-bottleneck node i.e. matrix metallopeptidase 9 (MMP9), a host protein corresponding to its upregulated gene. MMP9 showed functional annotations associated with neutrophil mediated immunoinflammation. Moreover, literature survey revealed that angiotensin converting enzyme 2, a membrane receptor of SARS-CoV-2 virus, might have functional cooperativity with MMP9 and a possible interaction with both drugs.
Significance:
The present study reveals that between chloroquine and melatonin, melatonin appears to be more promising repurposed drug against MMP9 for better immunocompromisation in COVID-19.
Insights
Melatonin shows promise as a repurposed drug for COVID-19, targeting matrix metallopeptidase 9 (MMP9) and aiding immunocompromisation. This study explored host protein targets for effective COVID-19 treatments.
Area of Science:
- * Computational biology
- * Network pharmacology
- * Virology
Background:
- * COVID-19 shares molecular pathogenesis with other coronaviruses (CoVs), including SARS.
- * Effective treatment strategies for COVID-19 are limited, necessitating exploration of host-targeted therapies.
- * Repurposed drugs offer a potential avenue for rapid therapeutic development.
Purpose of the Study:
- * To identify host proteins targeted by repurposed drugs in COVID-19.
- * To construct and analyze a protein-protein interaction (PPI) and chemo-protein interaction (CPI) network.
- * To evaluate potential therapeutic candidates based on network analysis.
Main Methods:
- * Identification of differentially expressed genes (DEGs) from SARS-CoV patient blood microarray data.
- * Selection of repurposed drugs for COVID-19 from existing literature.
- * Construction of integrated PPI-CPI networks to model drug-host protein interactions.
- * Analysis of network topology to identify hub-bottleneck nodes and associated proteins/drugs.
Main Results:
- * A network comprising 120 DEGs and 65 drugs was constructed.
- * A top-ranked sub-network identified 12 hub-bottleneck nodes, including matrix metallopeptidase 9 (MMP9).
- * Melatonin and chloroquine were associated with MMP9, with melatonin showing greater promise for immunocompromisation in COVID-19.
Conclusions:
- * Melatonin is a promising repurposed drug candidate for COVID-19, targeting MMP9.
- * MMP9, associated with neutrophil-mediated immunoinflammation, may be a key host target.
- * Functional cooperativity between MMP9 and angiotensin converting enzyme 2 (ACE2) is suggested, with potential drug interactions.
