Some viruses can enter inside cells through a mechanism that involves sulfur organic molecules. UNIGE chemists have found effective inhibitors and blocked the intake of SARS-CoV-2.
The cell membrane is impermeable to viruses: to enter and infect the cell, they use a number of strategies to exploit the cellular and biochemical properties of the membranes. Thiol-mediated uptake of alcohol-like organic molecules, where oxygen is replaced by sulfur atom, is one of the input mechanisms, with its use by the human immune deficiency virus (HIV), demonstrated several years ago. There is currently no effective inhibitor available due to the strength of chemical reactions and 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 most commonly used today. Preliminary tests – published and available free of charge through Chemical science, the leading journal of the Royal Society of Chemistry – demonstrates blocking the cellular entry of viruses expressing SARS-CoV-2 proteins. The research paves the way for research into new antivirals.
Since 2011, the laboratory, led by Professor Stefan Matil in the Department of Organic Chemistry at UNIGE, a member of the two National Centers for Competence in Research (NCCR), Chemical Biology and Molecular Systems Engineering, has been studying the way thiols react with others. structures containing sulfur: sulfides, molecules where sulfur combines with another chemical element. “These are very special chemical reactions because they can change their state dynamically,” Professor Matil began. In fact, covalent bonds based on the sharing of electrons between two atoms fluctuate freely between sulfur atoms, depending on the conditions.
Crossing 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 show that they play a role in one of the mechanisms – known as thiol-mediated uptake – that allows the very difficult passage from the outside to the inside of the cell. This key step involves the dynamic relationship between thiols and sulfides. “Everything that comes close to the cell can be linked to these dynamic sulfur bonds,” Professor Matil continued. “They cause the substrate to enter the cell either by fusion or endocytosis, or by direct translocation through 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 believes it was involved in cell digestion,” said the professor, who explained that this skepticism on the part of the scientific community was probably due to the lack of an available inhibitor 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, in part due to the relatively low reactivity of Ellman’s reagent, faced with the high reactivity of thiols and sulfides. “
The search for an inhibitor
While Stefan Matile’s lab was working on writing a bibliography on the subject during the first Swiss blockade in the spring of 2020, it began looking for a potential inhibitor, thinking it might be useful as an antiviral against SARS-CoV-2. . Professor Matile’s colleagues reviewed the potential inhibitors and performed in vitro tests for the uptake of sulfur-labeled cellular molecules by fluorescent probes to assess their presence in the 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 laboratory embarked on virus tests with the help of Neurix, a Geneva-based plant. They modified laboratory viruses called lentivators, expressing pandemic proteins from the SARS-CoV-2 virus envelope safely and harmlessly. One of the inhibitors has been shown to be effective in blocking the virus from entering cells in vitro. “These results are at a very early stage and it would be completely speculative to say that we have found an antiviral drug against coronavirus. At the same time, this study shows that thiol absorption may be an interesting line of study for the development of future antivirals, ”concludes Professor Matile.
Reference: Thiol Absorption Inhibitors by Yangyang Cheng, Anh-Tuan Pham, Takehiro Kato, Bumhee Lim, Dimitri Moreau, Javier López-Andarias, Lili Zong, Naomi Sakai and Stefan Matile, 18 November 2020, Chemical science.
DOI: 10.1039 / D0SC05447J