Researchers at the University of Dundee have revealed in the greatest detail yet the workings of molecules called “protein degraders” that can be used to combat what were previously considered “non-drug” diseases, including cancer and neurodegenerative diseases.
Protein-degrading molecules are heralding a revolution in drug discovery: more than 50 such drugs are currently being tested in clinical trials for patients with diseases for which there are no other options.
The Center for Targeted Protein Degradation (CeTPD) at the University of Dundee is one of the world’s leading centers for research into how protein degraders work and how they can be used more effectively for a new generation of drugs.
Now researchers have revealed previously invisible levels of detail and understanding of how protein degraders work, which in turn is enabling even more targeted use of them at the molecular level.
PhD student Charlotte Crowe, together with Dr Mark Nakasone, senior postdoctoral scientist at CeTPD, used a technique called cryo-electron microscopy (cryo-EM), which allows scientists to see how biomolecules move and interact with each other.
This works by freezing proteins instantly and using a focused electron beam and high-resolution camera to generate millions of 2D images of the protein. They then used sophisticated software and artificial intelligence (AI) models that allowed them to generate 3D snapshots of the degrading drugs working in action.
His latest research is published in the journal. Scientific advances and is expected to constitute a landmark contribution to research in the field of TPD and ubiquitin mechanisms.
“We have reached a level of detail where we can see how these protein degraders work and how they can be implemented [to recruit the disease-causing protein ] and target the ‘target’, in molecular terms,” said Charlotte Crowe, who carried out the research alongside a wider team of Dundee researchers.
“Protein degradation molecules work in a fundamentally different way to the way conventional drugs work. However, until recently, the exact details of how this process works at a molecular level were elusive.
“Proteins are typically a few nanometers in size, which is equivalent to a billionth of a meter, or a millionth of the width of a hair. Therefore, until now it has not been possible to ‘see’ them in action.
“We have now been able to create a moving image of how everything happens, which means we can more specifically control the process with an incredible level of detail.”
Professor Alessio Ciulli, Director of CeTPD and one of the world leaders in the field of selective protein degradation, said: “This is incredibly exciting work and opens up the possibility of developing even more effectively targeted drugs capable of eventually treating some diseases. that until now “It has been too difficult to address.”
how it works
Proteins are essential for our cells to function properly, but when they do not function properly they can cause diseases.
Targeted protein degradation involves redirecting the protein recycling systems in our cells to destroy disease-causing proteins.
Protein degraders work by capturing the disease-causing protein and causing it to stick like glue to the cellular protein recycling machinery, which then labels the protein as expired for destruction.
The tag is a small protein called ubiquitin, which effectively fires at the disease-causing protein like a bullet. For the process to work effectively, ubiquitin must reach the right spots on the target protein so that it is tagged effectively. The Dundee team’s new work allows them to see how the bullet hits the proverbial target.
Working with a protein-degrading molecule called MZ1, which was developed at Dundee’s Ciulli laboratory, and using high-end mass spectrometry, they were able to identify exactly where on the target protein the vital ‘tags’ are added.
The work shows how degrading drugs retain and position disease-causing proteins, making them good targets for receiving ubiquitin (i.e., “ubiquitinatable”) molecules that then lead to their destruction inside the cell.
The efficiency and productivity of protein degradation depends on the ability of the degrading molecule to retain the disease-causing protein and in a position where it can act most effectively. This latest research paints a target and keeps it stable enough for the molecule to aim accurately.
Professor Ciulli said this and other recently published papers were contributing to the rapid development of an exciting field of science and drug discovery.
“This rapidly expanding field is fascinating and the laboratories of biochemists Brenda Schulman (Max-Planck Institute for Biochemistry) and Gary Kleiger (University of Nevada, Las Vegas).
“Our collective work provides a breakthrough in understanding that will accelerate the development of new TPD drugs in the future.”