Searching for molecular glue in targeted disease control
There are some proteins at work in cells, and there are other proteins that regulate these working processes, the latter suppressing or enhancing the activity as needed. However, in many diseases, such as cancer, the regulatory proteins cannot keep pace with the large number of these activities. Researchers at Eindhoven University of Science and Technology developed a molecular glue in 2019 to help regulators inhibit it more quickly. Now that the technology has been further developed, allowing researchers to find a completely unexpected way for searching for new protein-binding molecules. For example, this technology provides a prospect for the development of drugs for cancer, diabetes or cystic fibrosis. These researchers published their results in Nature Letters.
Fig.1. Convert the signal molecule in such a way that it changed from inhibitor to stabilizer[1]
Overactive protein is the cause of many diseases in our body. Doctors usually fight these diseases directly by using inhibitors that target hyperactive proteins. However, this does not apply to all diseases. Drugs sometimes inhibit not only diseased proteins, but also healthy ones. As a result, researchers continue to look for other ways to inhibit overactive proteins without disturbing the healthy proteins.
Regulatory proteins provide a reasonable pathway because their natural function is to inhibit cell hyperactivity. If the inhibitory ability of those regulatory proteins can be supported by expanding the volume, then a more natural and effective way can be found to inhibit hyperactive proteins. Eline Sijbesma and Emira Visser at the Institute of Complex Molecular Systems have begun to study this problem.
Keys and locks
Because regulatory proteins bind to proteins that need to be regulated in cellular processes to form complexes, the activity in our cells is inhibited or magnified. According to Sijbesma, “the shape of the two proteins and where they bind to each other forms a cavity between the two proteins. It is these cavities that make the delivery of targeted drugs interesting. The cavity is very specific, for each complex of the two proteins, the available sites in the cavity are unique. For us, these are the chemical ways we target new drugs.”
The holes in the protein complex are bound by small signal molecules in the cell. They act as inhibitors (to ensure that other proteins cannot bind) or as stabilizers (to make the complex more stable). This stabilizer acts as a molecular glue that binds two proteins together so that they can communicate better. Regulatory proteins play a greater role in inhibiting processed proteins. Wayward disease proteins can therefore be forcefully corrected in a natural way.
"We want to make new stabilizers, and we need to make them so unique that they are only suitable for one compound," Visser explained. “Therefore, the key is to find a particle that happens to be suitable for that particular cavity, such as the key in the lock. Once you know how to do this, you can find the right cavity for each disease and develop very special molecules for it. "
Stabilizers and inhibitors
In 2019, researchers discovered an adhesive molecule that really fits the cavity of the protein complex, and its binding force to the regulator protein is 40 times stronger than without the glue. “Now that we have proved that our hypothesis is correct, we can look for new ways to find the chemical starting point of adhesive molecules. We start with a set of virtual molecules, and then we start to fix them to perfectly fit the complexity we thought of.” said Sijbesma.
However, researchers later discovered that one of the most promising molecules is a familiar inhibitor that prevents proteins from binding to regulatory proteins. This means that there is a larger library of possible molecules to choose from. “We haven't thought about this before because we don't want the properties of inhibitors, that is, there are no other proteins that can bind.” Visser said. After many modifications to the inhibitor molecules, they have shown that they can convert those undesired properties into the desired ones. "We actually turned the inhibitor into a stabilizer," Sijbesma explained. Sijbesma and Visser worried that the new molecule might not be specific enough to affect several protein complexes, but this was not the case after a great deal of experimental work. As a result, researchers have discovered a whole new molecular library that can be used as a starting point for molecular glue.
The next step is to test the new molecules in the cells. Eventually, the researchers hope to build a platform on which they can apply the same skills they will soon touch in the future to many different diseases, such as diabetes, neurodegenerative diseases, cystic fibrosis and various cancers. "These diseases are caused by wayward proteins and are so complex that direct inhibition is often not selective," Sijbesma concluded.
References
- Sijbesma, E., Visser, E., Plitzko, K., Thiel, P., Milroy, L. G., Kaiser, M., ... & Ottmann, C. (2020). Structure-based evolution of a promiscuous inhibitor to a selective stabilizer of protein–protein interactions. Nature communications, 11(1), 1-9.
- Mayor-Ruiz, C., Bauer, S., Brand, M., Kozicka, Z., Siklos, M., Imrichova, H., ... & Petzold, G. (2020). Rational discovery of molecular glue degraders via scalable chemical profiling. Nature Chemical Biology, 16(11), 1199-1207.
