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1.
Molecules ; 27(3)2022 Jan 27.
Article in English | MEDLINE | ID: covidwho-1674736

ABSTRACT

Butyrate is a major gut microbiome metabolite that regulates several defense mechanisms against infectious diseases. Alterations in the gut microbiome, leading to reduced butyrate production, have been reported in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A new butyrate releaser, useful for all the known applications of butyrate, presenting physiochemical characteristics suitable for easy oral administration, (N-(1-carbamoyl-2-phenyl-ethyl) butyramide (FBA), has been recently developed. We investigated the protective action of FBA against SARS-CoV-2 infection in the human small intestine and enterocytes. Relevant aspects of SARS-CoV-2 infection were assessed: infectivity, host functional receptor angiotensin-converting enzyme-2 (ACE2), transmembrane protease serine 2 (TMPRSS2), neuropilin-1 (NRP1), pro-inflammatory cytokines expression, genes involved in the antiviral response and the activation of Nf-kB nuclear factor (erythroid-derived 2-like) 2 (Nfr2) pathways. We found that FBA positively modulates the crucial aspects of the infection in small intestinal biopsies and human enterocytes, reducing the expression of ACE2, TMPRSS2 and NRP1, pro-inflammatory cytokines interleukin (IL)-15, monocyte chemoattractant protein-1 (MCP-1) and TNF-α, and regulating several genes involved in antiviral pathways. FBA was also able to reduce the number of SARS-CoV-2-infected cells, and ACE2, TMPRSS2 and NRP1 expression. Lastly, through the inhibition of Nf-kB and the up-regulation of Nfr2, it was also able to reduce the expression of pro-inflammatory cytokines IL-15, MCP-1 and TNF-α in human enterocytes. The new butyrate releaser, FBA, exerts a preventive action against SARS-CoV-2 infection. It could be considered as an innovative strategy to limit COVID-19.


Subject(s)
Butyrates/pharmacology , COVID-19/drug therapy , SARS-CoV-2/metabolism , Antiviral Agents/pharmacology , Butyrates/metabolism , COVID-19/metabolism , Caco-2 Cells , Enterocytes/drug effects , Enterocytes/metabolism , Gene Expression/genetics , Gene Expression Regulation/genetics , Humans , Intestines/drug effects , Intestines/metabolism , Male , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity
2.
Mol Biol Rep ; 48(5): 4667-4675, 2021 May.
Article in English | MEDLINE | ID: covidwho-1237535

ABSTRACT

The transmembrane protease serine 2 (TMPRSS2) is a membrane anchored protease that primarily expressed by epithelial cells of respiratory and gastrointestinal systems and has been linked to multiple pathological processes in humans including tumor growth, metastasis and viral infections. Recent studies have shown that TMPRSS2 expressed on cell surface of host cells could play a crucial role in activation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein which facilitates the rapid early entry of the virus into host cells. In addition, direct suppression of TMPRSS2 using small drug inhibitors has been demonstrated to be effective in decreasing SARS-CoV-2 infection in vitro, which presents TMPRSS2 protease as a potential therapeutic strategy for SARS-CoV-2 infection. Recently, SARS-CoV-2 has been shown to be capable of infecting gastrointestinal enterocytes and to provoke gastrointestinal disorders in patients with COVID-19 disease, which is considered as a new transmission route and target organ of SARS-CoV-2. In this review, we highlight the biochemical properties of TMPRSS2 protease and discuss the potential targeting of TMPRSS2 by inhibitors to prevent the SARS-CoV-2 spreading through gastro-intestinal tract system as well as the hurdles that need to be overcome.


Subject(s)
COVID-19/metabolism , Enterocytes/drug effects , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Evaluation, Preclinical , Enterocytes/metabolism , Enterocytes/virology , Humans , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization/drug effects
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