Secondary metabolites of Alternaria alternate appraisal of their SARS-CoV-2 inhibitory and anti-inflammatory potentials
Fatma A Moharram, Reham R Ibrahim, Shahenda Mahgoub, Mohamed S Abdel-Aziz, Ahmed M Said, Hui-Chi Huang, Lo-Yun Chen, Kuei-Hung Lai, Nashwa Hashad, Mohamed S Mady
PLOS ONE, doi:10.1371/journal.pone.0313616
This study identifies the secondary metabolites from Alternaria alternate and evaluates their ACE-2: Spike RBD (SARS-CoV-2) inhibitory activity confirmed via immunoblotting in human lung microvascular endothelial cells. In addition, their in vitro anti-inflammatory potential was assessed using a cell-based assay in LPS-treated RAW 264.7 macrophage cells. Two novel compounds, altenuline (1), phthalic acid bis (7'/7'' pentyloxy) isohexyl ester (2), along with 1-deoxyrubralactone (3) alternariol-5-O-methyl ether (4) and alternariol (5) were identified. Molecular docking and in vitro studies showed that compounds 2 and 4 were promising to counteract SARS-CoV-2 attachment to human ACE-2. Thus, they are considered promising natural anti-viral agents. SwissADME in silico analysis was conducted to predict the drug-like potential. Immunoblotting analysis confirmed that the tested compounds (1-4) demonstrated downregulation of ACE-2 expression in the endothelial cells from the lungs with variable degrees. Furthermore, the tested compounds (1-4) showed promising antiinflammatory activities through TNF-α: TNFR2 inhibitory activity and their inhibitory effect on the proinflammatory cytokines (TNF-α and IL-6) in LPS-stimulated monocytes. In conclusion, our study, for the first time, provides beneficial experimental confirmation for the efficiency of the A. alternate secondary metabolites for the treatment of COVID-19 as they hinder SARS-CoV-2 infection and lower inflammatory responses initiated by SARS-CoV-2. A. alternate and its metabolites are considered in developing preventative and therapeutic tactics for COVID-19.
Supporting information S1
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doi:10.3389/fimmu.2020.576745DOI record:
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"abstract": "<jats:p>This study identifies the secondary metabolites from <jats:italic>Alternaria alternate</jats:italic> and evaluates their ACE-2: Spike RBD (SARS-CoV-2) inhibitory activity confirmed <jats:italic>via</jats:italic> immunoblotting in human lung microvascular endothelial cells. In addition, their <jats:italic>in vitro</jats:italic> anti-inflammatory potential was assessed using a cell-based assay in LPS-treated RAW 264.7 macrophage cells. Two novel compounds, altenuline (<jats:bold>1</jats:bold>), phthalic acid bis (7’/7’’ pentyloxy) isohexyl ester (<jats:bold>2</jats:bold>), along with 1-deoxyrubralactone (<jats:bold>3</jats:bold>) alternariol-5-<jats:italic>O</jats:italic>-methyl ether (<jats:bold>4</jats:bold>) and alternariol (<jats:bold>5</jats:bold>) were identified. Molecular docking and <jats:italic>in vitro</jats:italic> studies showed that compounds <jats:bold>2</jats:bold> and <jats:bold>4</jats:bold> were promising to counteract SARS-CoV-2 attachment to human ACE-2. Thus, they are considered promising natural anti-viral agents. SwissADME in silico analysis was conducted to predict the drug-like potential. Immunoblotting analysis confirmed that the tested compounds (<jats:bold>1–4</jats:bold>) demonstrated downregulation of ACE-2 expression in the endothelial cells from the lungs with variable degrees. Furthermore, the tested compounds (<jats:bold>1–4</jats:bold>) showed promising anti-inflammatory activities through TNF-α: TNFR2 inhibitory activity and their inhibitory effect on the proinflammatory cytokines (TNF-α and IL-6) in LPS-stimulated monocytes. In conclusion, our study, for the first time, provides beneficial experimental confirmation for the efficiency of the <jats:italic>A</jats:italic>. <jats:italic>alternate</jats:italic> secondary metabolites for the treatment of COVID-19 as they hinder SARS-CoV-2 infection and lower inflammatory responses initiated by SARS-CoV-2. <jats:italic>A</jats:italic>. <jats:italic>alternate</jats:italic> and its metabolites are considered in developing preventative and therapeutic tactics for COVID-19.</jats:p>",
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