Some viruses can enter cells via a mechanism involving organic sulfur molecules. UNIGE chemists have discovered effective inhibitors and blocked the absorption of SARS-CoV-2.
The cell membrane is impermeable to viruses: to get inside and infect a cell, they use a range of strategies to harness the cellular and biochemical properties of membranes. The thiol-mediated absorption of organic molecules similar to alcohols, where oxygen is replaced by sulfur atom, is one of the entry mechanisms, with its use by the 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 at work. A research group at the University of Geneva (UNIGE) has identified inhibitors up to 5,000 times more effective than the one most often used today. Preliminary tests – published and freely available in Chemical science, the flagship journal of the Royal Society of Chemistry – demonstrates the blockade of cellular entry of viruses expressing the proteins of SARS-CoV-2. The study paves the way for the search for new antivirals.
Since 2011, the laboratory headed by Professor Stefan Matile from the Department of Organic Chemistry at UNIGE, member of the two National Research Competence Centers (NCCR), Chemical Biology and Molecular Systems Engineering, has been studying the way thiols react with d ‘other structures containing sulfur: sulphides, molecules where sulfur is combined with another chemical element. “These are very special chemical reactions because they can change state dynamically,” explains Professor Matile. In fact, covalent bonds, based on the sharing of electrons between two atoms, oscillate freely between sulfur atoms, depending on the conditions.
Pass the cell membrane
Sulfur compounds are present in nature, in particular 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 – called thiol-mediated absorption – that allows very difficult passage from the outside to the inside of the cell. This key step involves the dynamic bond between thiols and sulfides. “Anything that approaches the cell can connect to these dynamic sulfur bonds,” continues Professor Matile. “They bring the substrate into the cell either by fusion or endocytosis, or by direct translocation through the plasma membrane in 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 thinks that it was involved in cell uptake,” explains the professor, who explains that this skepticism in the scientific community is probably due to the lack of inhibitor available to test it. “The involvement of membrane thiols in cellular uptake is generally tested by inhibition using Ellman’s reagent. Unfortunately, this test is not always reliable, in part due to the relatively low reactivity of Ellman’s reagent to the high reactivity of thiols and sulfides.
The quest for an inhibitor
While Stefan Matile’s laboratory was working on writing a bibliographic review on the subject during the first Swiss lockout in spring 2020, it set out to search for a potential inhibitor, believing that it could be ‘prove useful as an antiviral against SARS-CoV-2. Prof. Matile’s colleagues reviewed potential inhibitors and performed in vitro cellular uptake assays of labeled sulfur molecules with fluorescent probes to assess their presence inside cells using handheld microscopy. fluorescence.
Molecules up to 5,000 times more effective than Ellman’s reagent have been identified. With these excellent inhibitors in hand, the laboratory embarked on viral tests with the help of Neurix, a Geneva start-up. They have engineered laboratory viruses, called lentivectors, expressing the proteins of the pandemic SARS-CoV-2 viral envelope safely and harmlessly. One of the inhibitors was found to be effective in blocking entry of the virus 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 the coronavirus. At the same time, this research shows that thiol-mediated absorption could be an interesting avenue for the development of future antivirals ”, concludes Professor Matile.
Reference: “Inhibitors of thiol-mediated absorption” 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