Some viruses can enter cells via a mechanism that includes organic sulfur particles. Chemists at UNIGE discovered effective inhibitors that blocked SARS-CoV-2 from being absorbed.
Credit: © UNIGE / MATILE.
The cell membrane is impermeable for viruses: to enter and infect the cell, they use a range of strategies to exploit the cellular and biochemical properties of the membranes. One of the entry mechanisms is the absorption of thiol mediated by organic molecules similar to the alcohol, as oxygen is replaced by sulfur atom, with its use by the human immunodeficiency virus (HIV) some years ago. There is no effective inhibitor currently available due to the durability of chemical reactions and bonds at work. A research group from the University of Geneva (UNIGE) has identified inhibitors up to 5,000 times more effective than the ones most used today. Initial tests – published and freely available at Chemical sciences, The flagship journal of the Royal Society of Chemistry – Explains the cellular ingress of viruses expressing SARS-CoV-2 proteins. The study paves the way for research into new antivirals.
Since 2011, the laboratory led by Professor Stefan Mattel in the Department of Organic Chemistry at UNIGE, a member of the National Centers for Research Competence (NCCR) “Chemical Biology” and “Molecular Systems Engineering”, has been studying the way thiols interact with others in the structures that contain Sulfur: Sulfur molecules where sulfur is combined with another chemical element. Professor Mattel begins: “These are very special chemical reactions because they can change their state dynamically.” In fact, covalent bonds, based on the sharing of electrons between two atoms, oscillate freely between the sulfur atoms, depending on the conditions.
Traversing the cell membrane
Sulfur compounds are found in nature, especially on the membranes of eukaryotic cells and on the coatings of viruses, bacteria, and toxins. Studies show that it plays a role in one of the mechanisms – known as thiol-mediated absorption – that enables extremely difficult passage from outside into the cell. This major step involves the dynamic bond between thiols and sulfides. “Everything that comes close to the cell can connect with these dynamic sulfur bonds,” continues Professor Mattel. “They cause the substrate to enter the cell, either by fusion or endocytosis, or by direct transmission through the plasma membrane to the cytosol.” Studies a few years ago showed that the entry of HIV and diphtheria toxin used a mechanism involving thiols.
“This chemistry is well known, but nobody thinks it was involved in cellular uptake,” says the professor, who explains that this suspicion on the part of the scientific community may be due to the lack of an inhibitor available to test. “The involvement of membrane thiols in cellular uptake is usually tested by inhibition with Ellman’s reagent. Unfortunately, this test is not always reliable, in part due to the relatively low reactivity of Ellman’s reagent which experiences the high interaction of thiol and sulfides.
The pursuit of inhibitor
While Stefan Matile’s lab was working on writing a bibliographic review on the topic during the first Swiss lockdown in Spring 2020, it began looking for a potential inhibitor, believing it could be useful as an antiviral against SARS-CoV-2. Professor Mattel’s co-workers have reviewed potential inhibitors and performed in vitro cytological uptake assays of the sulfur particles labeled with a fluorescent probe to assess their presence within cells using fluorescence microscopy.
Molecules have been identified up to 5,000 times more effective than Ellman’s reagent. With these excellent inhibitors on hand, the lab has thrown itself into viral tests with the help of Neurix, a Geneva-based startup. They modified laboratory viruses, called lentivectors, expressing the pandemic envelope proteins SARS-CoV-2 safely and without harm. One of the inhibitors was found to be effective in preventing the virus from entering cells in the laboratory. “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 area of research for developing future antivirals,” says Professor Mattel.