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The cell membrane is impermeable to viruses: to enter and infect a cell, they use a series of strategies to exploit the cellular and biochemical properties of the membranes. Thiol-mediated absorption of alcohol-like organic molecules, where oxygen is replaced by a sulfur atom, is one of the mechanisms of entry, with its use by the human immunodeficiency virus (HIV) proven some years does. No effective inhibitors are currently available due to the robustness of the chemical reactions and the bonds at work. A research team from the University of Geneva (UNIGE) has identified inhibitors that are up to 5,000 times more effective than the one most often used today. Preliminary tests – published and available for free in Chemical sciences, the flagship journal of the Royal Society of Chemistry – demonstrate cellular entry blocking of viruses that express SARS-CoV-2 proteins. The study paves the way for the search for new antivirals.
Since 2011, the laboratory led by Professor Stefan Matile of the UNIGE Department of Organic Chemistry, a member of the two National Centers of Competence in Research (NCCR) Chemical Biology and Molecular Systems Engineering, has been studying how thiols react with other structures containing sulfur: sulphides, molecules in which sulfur is combined with another chemical element. «They are very particular chemical reactions because they can change state dynamically», Professor Matile begins. In fact, the covalent bonds, based on the sharing of electrons between two atoms, oscillate freely between the sulfur atoms, depending on the conditions.
Passage of the cell membrane
Sulfur compounds occur naturally, particularly on the membrane of eukaryotic cells and the envelope of viruses, bacteria and toxins. Studies suggest that they play a role in one of the mechanisms – known as thiol-mediated absorption – that allows for very difficult passage from outside to inside the cell. This key step involves the dynamic link between thiols and sulfides. ‘Anything that comes close to the cell can connect to these dynamic sulfur bonds,’ continues Professor Matile. “They get the substrate into the cell by fusion or endocytosis, or by direct translocation across the plasma membrane into the cytosol.” Studies from a few years ago showed that HIV and diphtheria toxin entry use a mechanism involving thiols.
“This chemistry is well known, but no one believes it was involved in cell uptake,” says the professor, who explains that this skepticism on the part of the scientific community is likely due to the lack of inhibitors available to test it. “The involvement of membrane thiols in cell uptake is usually tested by inhibition using Ellman’s reagent. Unfortunately, this test is not always reliable, partly due to the relatively low reactivity of Ellman’s reagent in the face of the high reactivity of thiols and sulphides “.
The search for an inhibitor
While Stefan Matile’s lab was working on writing a literature review on the subject during the first Swiss block in spring 2020, it began looking for a potential inhibitor, thinking it might prove useful as an antiviral against SARS-CoV-2. Professor Matile’s colleagues examined potential inhibitors and conducted in vitro cell uptake tests of fluorescent-tagged sulfur molecules to assess their presence within cells using fluorescence microscopy.
Molecules up to 5,000 times more effective than Ellman’s reagent have been identified. With these excellent inhibitors in hand, the lab launched into viral testing with the help of Neurix, a Geneva-based start-up. They modified laboratory viruses, called lentivectors, that express proteins from the SARS-CoV-2 viral pandemic in a safe and harmless way. One of the inhibitors was found to be effective in blocking virus entry into cells in vitro. “These results are at a very early stage and it would be entirely speculative to say that we have discovered an antiviral drug against the coronavirus. At the same time, this research shows that thiol-mediated uptake could be an interesting line of investigation for development. future. antivirals “, concludes Professor Matile.
Reference: Cheng Y, Pham AT, Kato T, et al. Inhibitors of thiol-mediated absorption. Chem Sci. 2021. doi: 10.1039 / D0SC05447J
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