Researchers at the University of Dundee are delving into the intricate workings of protein degraders, molecules that show promise in treating diseases that were previously considered ‘undruggable,’ such as certain cancers and neurodegenerative diseases. These protein degraders are currently being tested in over 50 clinical trials for patients who have exhausted other treatment options. The Centre for Targeted Protein Degradation at the University of Dundee is at the forefront of this research, aiming to optimize the use of protein degraders for the development of a new generation of drugs.
The team of researchers, led by PhD student Charlotte Crowe and Dr. Mark Nakasone, has made significant strides in understanding the mechanisms of protein degraders using cryo-electron microscopy. This advanced technique allows scientists to observe biomolecules in action by freezing proteins and capturing images with a high-resolution camera. By utilizing sophisticated software and artificial intelligence models, the researchers were able to generate 3D snapshots of protein degraders in action. Their groundbreaking findings, published in the journal Science Advances, are expected to make a significant contribution to the field of targeted protein degradation.
Protein degraders function differently from traditional drugs by targeting specific disease-causing proteins and recruiting the cellular protein-recycling machinery to destroy them. These molecules work by attaching to the target protein and guiding it to the protein-recycling machinery, where it is tagged with a small protein called ubiquitin. The ubiquitin tag marks the protein as expired and triggers its destruction within the cell. Through their research, the Dundee team was able to identify the precise locations on the target protein where the crucial ubiquitin tags are added, shedding light on the intricate process of protein degradation.
The team focused on a protein degrader molecule called MZ1, developed in the Ciulli laboratory at Dundee, to study the tagging process with high-end mass spectrometry. Their findings revealed how degrader drugs anchor disease-causing proteins in position to receive ubiquitin molecules, ensuring their efficient and targeted destruction within the cell. The ability of protein degraders to effectively hold onto and position disease-causing proteins is essential for the success of targeted protein degradation and the development of new drugs to combat challenging diseases.
Professor Alessio Ciulli, a leading figure in the field of targeted protein degradation and Director of CeTPD, expressed excitement over the potential of this research to pave the way for more effective and precise drug treatments for diseases that have been difficult to tackle. The recent findings, combined with other studies in the field, are accelerating the development of new TPD drugs. Collectively, these advancements are enhancing our understanding of the cellular protein-recycling machinery and the process of targeting proteins for destruction, ultimately driving progress in scientific research and drug discovery.
The detailed insights gained from this research offer a new level of control and specificity in targeting disease-causing proteins with protein degraders. By visualizing the molecular interactions involved in protein degradation, researchers are poised to develop more tailored and effective drugs for diseases that have previously posed significant challenges. This groundbreaking work at the University of Dundee is contributing to the rapid advancement of targeted protein degradation as a promising avenue for innovative drug discovery and treatment strategies.
