Matrix metallopeptidase 9 as a host protein target of chloroquine and melatonin for immunoregulation in COVID-19: A network-based meta-analysis

Life Sci. 2020 Sep 15;257:118096. doi: 10.1016/j.lfs.2020.118096. Epub 2020 Jul 15.


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.

Keywords: COVID-19; Chloroquine; Coronavirus; MMP9; Melatonin; PPI-CPI network; SARS-CoV-2.

Publication types

  • Meta-Analysis

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Antiviral Agents / therapeutic use
  • Betacoronavirus / drug effects*
  • Betacoronavirus / metabolism
  • Betacoronavirus / pathogenicity
  • COVID-19
  • COVID-19 Drug Treatment
  • Chloroquine / pharmacology
  • Computational Biology / methods
  • Coronavirus Infections / drug therapy
  • Coronavirus Infections / metabolism*
  • Coronavirus Infections / physiopathology
  • Humans
  • Matrix Metalloproteinase 9 / metabolism
  • Melatonin / pharmacology
  • Metalloproteases / metabolism
  • Pandemics
  • Peptidyl-Dipeptidase A
  • Pneumonia, Viral / metabolism*
  • Pneumonia, Viral / physiopathology
  • Protein Interaction Maps / drug effects*
  • Protein Transport
  • SARS-CoV-2


  • Antiviral Agents
  • Chloroquine
  • Metalloproteases
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Matrix Metalloproteinase 9
  • Melatonin