Some viruses can enter cells via a mechanism involving organosulfur molecules. Chemists at UNIGE have discovered effective inhibitors and blocked their uptake SARS-CoV-2.
The cell membrane is impermeable to viruses: in order to enter and infect a cell, they use a variety of strategies to exploit the cellular and biochemical properties of the membranes. The thiol-mediated uptake of organic molecules similar to alcohols, where oxygen is replaced by a sulfur atom, is one of the entry mechanisms, with the use of Human Immunodeficiency Virus (HIV) demonstrated a few years ago. No effective inhibitor is currently available due to the robustness of the chemical reactions and bonds in the workplace. A research group from the University of Geneva (UNIGE) has identified inhibitors that are up to 5,000 times more effective than the one commonly used today. Preliminary tests – published and available free of charge in Chemical science, the flagship diary of the Royal Society of Chemistry – demonstrates blocking cellular entry of viruses expressing the SARS-CoV-2 proteins. The study paves the way for research into new antiviral drugs.
Since 2011, the laboratory, led by Professor Stefan Matile of UNIGE’s 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: , molecules where sulfur is combined with another chemical element. “These are very special chemical reactions because they can change state dynamically,” begins Professor Matile. In fact, covalent bonds based on dividing electrons between two atoms oscillate freely between sulfur atoms, depending on the conditions.
Passes the cell membrane
Sulfur compounds are present in nature, especially on the membrane of eukaryotic cells and on the envelope of viruses, bacteria and toxins. Studies suggest that they play a role in one of the mechanisms – known as thiol-mediated uptake – that allows the very difficult passage from the outside into the cell. This key step involves the dynamic bonding between thiols and sulfides. “Everything that approaches the cell can connect to these dynamic sulfur bonds,” continues Professor Matile. “They cause the substrate to enter the cell either by fusion or endocytosis or by direct translocation through plasma membrane into the cytosol. “Studies a few years ago showed that the entry of HIV and diphtheria toxin uses a mechanism involving thiols.
“This chemistry is well known, but no one believes it was involved in cellular uptake,” says the professor, explaining that this skepticism from the scientific community is probably due to the lack of inhibitor available to test it. “The involvement of membrane thiols in cellular uptake is usually tested by inhibition using Ellman’s reagent. Unfortunately, this test is not always reliable, in part because of the relatively low reactivity of Ellman’s reagent to the high reactivity of thiols and sulfides. ”
The hunt for an inhibitor
While Stefan Matile’s laboratory was working on a bibliographic review of the subject during the first Swiss shutdown in the spring of 2020, it began looking for a potential inhibitor and thought it might prove useful as an antiviral against SARS-CoV-2. Professor Matile’s colleagues reviewed potential inhibitors and performed in vitro cellular uptake tests of sulfur molecules marked with fluorescent probes to assess their presence inside cells using fluorescence microscopy.
Molecules up to 5,000 times more efficient than Ellman’s reagent were identified. With these excellent inhibitors in hand, the laboratory threw itself into viral testing using Neurix, a Geneva-based startup. The modified laboratory viruses, called lentivectors, that express the proteins of the SARS-CoV-2 viral envelope pandemic safely and harmlessly. One of the inhibitors was shown to be effective in blocking virus entry into cells in vitro. “These results are at a very early stage and it would be quite speculative to say that we have discovered an antiviral drug against coronavirus. At the same time, this research shows that thiol-mediated uptake could be an interesting line of study for the development of future antiviral drugs, ”concludes Professor Matile.
Reference: “Inhibitors of thiol-mediated recording” by Yangyang Cheng, Anh-Tuan Pham, Takehiro Kato, Bumhee Lim, Dimitri Moreau, Javier López-Andarias, Lili Zong, Naomi Sakai and Stefan Matile, November 18, 2020, Chemical science.
DOI: 10.1039 / D0SC05447J