Toolbox to Study Ligand Binding for Enhanced Treatments

Researchers at the Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland have developed a DNA toolkit that allows researchers to explore binding interactions between their ligands and receptors based on receptor density and arrangement. The basis of many drug-cell interactions, and indeed many physiological or pathological interactions involving biological signaling molecules, involves a molecule, called a ligand, that binds to a receptor normally present on the cell membrane. This link is very specific, but it can be affected by the density of links present. However, this latest research also sheds light on some other underappreciated factors that can significantly influence ligand/receptor binding, including ligand order and structural rigidity. To test these interactions and pave the way for more effective therapies, the researchers created a DNA-based toolkit that allows them to test factors that influence association more easily.

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Ligand/receptor binding is an essential biological process that can be exploited by humans and pathogens for their own ends. In the case of humans, we usually develop drugs to target specific receptors to achieve a therapeutic effect. In the case of certain viruses, they can bind to receptors as a way to get inside our cells. SARS-CoV-2 binds to ACE-2 receptors to reach nose and lung cells, for example. Understanding these processes in more detail allows us to influence them in beneficial ways, such as by preventing the virus from entering cells.

Diagram depicting different types of binding reactions © Bastings / PBL EPFL

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“When binding is triggered by a threshold density of target receptors, we call this ‘super selective’ binding, and it is key to preventing random interactions that can lead to abnormalities in biological function,” said Maartje Bastings, co-author of the study. “Since nature does not usually overcomplicate things, we wanted to find out the minimum number of binding interactions that would still allow super-selective binding to occur. We were also interested to see if the pattern in which the bonding molecules are arranged makes a difference in selectivity. As it turns out, Is also! “

Original microscopy data on different patterns of bonding on DNA materials © Bastings / PBL EPFL

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To study the binding interactions, the researchers created a tweak of DNA. DNA is well understood, and so the researchers chose it as a way to study linkage. They also knew how to engineer the disk so that they could control the exact number and pattern of links on it. The researchers had already determined that six links was the ideal number to ensure super-selective binding, but using their new toolkit they also discovered that the arrangement of links, whether it be in a line, triangle or circle, also has a significant effect on binding. They called this process “multivalent pattern recognition”.

Geometric ligand patterns of hexavalent versus random (far right) © Bastings/PBL EPFL

“Like it or not, SARS-CoV-2 is a first clue right now when it comes to viral applications,” Bastings said. “With the insights from our study, one could envision developing a highly selective particle with binding patterns designed to bind to the virus to prevent infection, or to block the location of the cell so that the virus cannot infect.”

Top image: visualization of protein intricacy at the cell surface © PBL EPFL / Christine Lavanchy

The study in Journal of the American Chemical Society: Recognizing multivalent patterns by controlling nanoscale spacing in low-valent superselective materials

Via: Ecole Polytechnique Fédérale de Lausanne


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