Abstract
Human intestinal epithelial cell line-6 (HIEC-6) cells and primary human hepatocytes (PHHs) were treated with 3-amidinophenylalanine-derived inhibitors of trypsin-like serine proteases for 24 hours. It was proven that treatment with MI-1900 and MI-1907 was tolerated up to 50 μM in HIEC-6. These inhibitors did not cause elevations in extracellular H2O2 levels and in the concentrations of interleukin (IL)-6 and IL-8 and did not alter occludin distribution in HIEC-6. It was also found that MI-1900 and MI-1907 up to 50 μM did not affect cell viability, IL-6 and IL-8 and occludin levels of PHH. Based on our findings, these inhibitors could be safely applicable at 50 μM in HIEC-6 and in PHH; however, redox status was disturbed in case of PHH. Moreover, it has recently been demonstrated that MI-1900 prevents the replication and spread of the new SARS-CoV-2 in infected Calu-3 cells, most-likely via an inhibition of the membrane-bound host protease TMPRSS2.
Keywords:
H2O2; HIEC-6; PHH; occludin; trypsin-like serine protease inhibitors.
MeSH terms
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Antiviral Agents / pharmacology*
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Cell Line
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Cell Survival / drug effects
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Epithelial Cells / cytology
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Epithelial Cells / drug effects*
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Epithelial Cells / enzymology
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Gene Expression Regulation / drug effects
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Hepatocytes / cytology
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Hepatocytes / drug effects*
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Hepatocytes / enzymology
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Humans
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Hydrogen Peroxide / metabolism
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Interleukin-8 / genetics
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Interleukin-8 / metabolism
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Intestinal Mucosa / cytology
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / enzymology
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Occludin / genetics
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Occludin / metabolism
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Oxidation-Reduction / drug effects
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Phenylalanine / analogs & derivatives
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Phenylalanine / pharmacology*
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Primary Cell Culture
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Protease Inhibitors / pharmacology*
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism*
Substances
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Antiviral Agents
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IL6 protein, human
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Interleukin-6
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Interleukin-8
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OCLN protein, human
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Occludin
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Protease Inhibitors
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trypsin-like serine protease
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Phenylalanine
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Hydrogen Peroxide
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Serine Endopeptidases
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TMPRSS2 protein, human
Grants and funding
This work was supported by the Hungarian National Research, Development and Innovation Office under Grant 115685 and 124522; and the European Union and Co-Financed by the European Social Fund under Grant Agreement No. EFOP-3.6.1-16-2016-00024 and EFOP-3.6.3-VEKOP-16-2017-00005, project title: Strengthening the scientific replacement by supporting the academic workshops and programs of students, developing a mentoring process. This project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and by the ÚNKP-20-5 New National Excellence Program of the Ministry for Innovation and Technology from the Source of the National Research, Development and Innovation Fund.