Like charges repel, and opposite charges attract. The more positive and negative charges meet, the stronger this electrostatic attraction is. Scientists like Professor Rainer Haag refer to this phenomenon as “multivalent interactions.” Researchers been investigating it at Freie Universität Berlin for more than ten years within the Collaborative Research Center SFB 765 “Multivalency as chemical organization and action principle: New architectures, functions and applications.” Haag, a polymer chemist, explains, “We work primarily on the interaction of charged molecules and biological surfaces, especially with the question of how viruses bind to the cell surface and how this can be prevented.”

Most viruses use charge interactions for their first contact with the host cell. This is also the case with the coronavirus, which has proteins that are highly positively charged. They are attracted to human cells whose surfaces are heavily studded with negatively charged sugar chains called heparan sulfate chains. This is how SARS-CoV2 gets its “foot in the door” before its spike protein binds to the ACE2 enzyme on the cell membrane.

Berlin Research Landscape United against SARS-CoV2

As early as the beginning of 2020, Rainer Haag’s team began investigating SARS-CoV2 and its variants as part of a large Berlin joint coronavirus project. The recently completed Corona Virus Pre-Exploration Project, funded by the Berlin University Alliance with 1.8 million euros, aimed, among other things, at developing and testing antiviral therapies and prevention approaches. Together with the main applicants Professor Rainer Haag and Professor Christian Drosten, the director of the Institute for Virology at Charité – Universitätsmedizin Berlin, 16 researchers from the Berlin research landscape are involved. They work in the fields of chemistry, virology, biophysics, veterinary medicine, and pulmonology.

More Positively Charged Amino Acids Mean Better Adhesion and More Spread

The positive charges of the coronavirus come from amino acids in the spike protein – lysine, arginine, and histidine – which are positively charged under physiological conditions. “We took a closer look at the amino acid sequences of the spike protein of all coronavirus mutants and found that the delta variant has four more positively charged amino acids per spike than the wild type, i.e., the original Wuhan variant. The omicron variant even has nine more positively charged amino acids,” says Haag. “Therefore it is logical that omicron interacts more strongly with the cells and can attach itself better. That could explain why the omicron variant is more contagious.”

Inhalation Therapy Is Being Considered

Haag says this is basically good news. For several years he has been developing synthetic polysulfanes together with Canadian colleagues as part of the International Research Training Group “Charging into the Future.” The idea is that the synthetic polysulfanes would prevent viruses from making initial contact with cells. Inhalation therapy is currently under consideration. It would be simplest to mimic the cell’s heparan sulfate, which closely resembles natural heparin. “Clinical studies are currently being carried out in Israel to determine whether heparin can be inhaled. But there are two problems,” explains Haag. “On the one hand, heparin must never be overdosed because it is an anticoagulant and has the potential risk of causing bleeding. On the other hand, it is not effective enough.” The artificial polysulfanes developed as an alternative are two to three powers of ten more effective than heparin.

The basis for this are molecular strands made of polyglycerols. These are linked glycerin molecules, each of which carries a sulfate group per unit. “Each of these sulfates can therefore capture a positive charge on the spike protein,” explains Haag. If the polyglycerol were used as a nasal spray, the virus would no longer be able to see the forest for the trees, so to speak, and would get caught in the active substance instead of in the cells.

Polysulfates Effective against All Viruses That Attach to Their Host Cells Electrostatically

Haag says that taking it in through the nose and throat, all the way to the lungs, has the great advantage that the active substance can be used where it is supposed to go. Given prophylactically, such a spray could prevent a coronavirus infection. Haag points out that there is no danger that polysulphates would lose their effectiveness if the virus continues to mutate. “The ability to interact between charges is vital for the virus to survive. If it could no longer bind to the heparans on the cell surfaces, it would no longer be so infectious.”

The effectiveness has already been proven in cell cultures, and the polysulphates are also well tolerated. In lung cell cultures, the scientists have seen that the concentration needed for virus blockade is three powers of ten below what would be toxic for the cells. The researchers within the Berlin University Alliance are currently developing a three-dimensional lung model for further tests. This will be followed by studies in animal models. There are also initial contacts with the pharmaceutical industry.

The necessary clinical studies on humans are expensive and lengthy, so the new product will not be any help for this pandemic. Nonetheless, the findings are valuable because the active principle is so universal that it will also help against infection with many other viruses, such as RSV and the “normal” coronaviruses, i.e., against all those that dock to their host cells via electrostatic interactions. The spray could become a “must have” in autumn and winter, possibly as an alternative to the mask.

Start-up Supported by the University

Another product developed according to this principle can be ready for use much faster. “Virus scavengers” in the form of a coating for air filter systems only require a TÜV certificate. The concept for them was developed and patented in the Haag group. A start-up company, NoVirall, led by postdoctoral researcher Paria Pouyan in Rainer Haag’s group, is being funded by the German Federal Ministry of Economics and Climate Protection through the EXIST Research Transfer program with 950,000 euros. The funding is needed to bring the coating to market maturity. The coating consists of a positively charged adhesive layer to which a negatively charged virucide is applied, and this imitates the human cell surface. Using the immersion method, both layers can be applied to any filter material and destroy the cell membranes of the captured viruses within two hours. It’s amazing, how easy it can be to fight viruses!

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This text originally appeared in German on February 26, 2022, in the Tagesspiegel newspaper supplement published by Freie Universität Berlin.