Targeted protein degradation has introduced a groundbreaking approach to drug discovery, offering new avenues for treating diseases that were previously deemed ‘undruggable.’ This innovative strategy allows for highly precise targeting of new drugs at the molecular level, akin to hitting a figurative ‘bull’s eye.’
Scientists from the University of Dundee have uncovered, in unparalleled detail, the mechanisms of molecules known as ‘protein degraders.’ These molecules can be utilized to address diseases that were long considered ‘undruggable,’ including various forms of cancer and neurodegenerative disorders.
Protein degraders are transforming drug development, with over 50 such drugs currently undergoing clinical trials for patients facing diseases without viable treatments.
The Centre for Targeted Protein Degradation (CeTPD) at the University of Dundee is among the top global institutions researching how protein degraders function and how they can be employed effectively for a new generation of medications.
The latest findings reveal previously unseen layers of complexity in the operation of protein degraders, enhancing their targeted application at the molecular scale.
PhD candidate Charlotte Crowe, alongside Dr. Mark Nakasone, a Senior Postdoctoral Scientist at CeTPD, utilized cryo-electron microscopy (cryo-EM). This advanced technique allows scientists to observe the movement and interaction of biomolecules.
The process involves flash-freezing proteins and employing a focused electron beam combined with a high-resolution camera to produce millions of 2D images. These images are then analyzed using sophisticated software and artificial intelligence (AI) models to create 3D representations of the protein degraders in action.
Their recent study is published in the journal Science Advances and is anticipated to be a significant contribution to research in targeted protein degradation (TPD) and ubiquitin mechanisms.
“We have attained a remarkable level of detail, allowing us to visualize how these protein degraders operate and can recruit disease-causing proteins, effectively targeting the ‘bull’s eye’ at the molecular level,” Charlotte Crowe remarked, reflecting on her research conducted with a broader group of Dundee researchers.
“Unlike traditional drugs, protein degraders function using fundamentally different mechanisms. However, the intricate details of this process at the molecular level have been elusive until now.
“Proteins are typically only a few nanometers in size, which is one billionth of a meter, or one millionth of the width of a human hair. Thus, capturing their dynamic activity has been challenging until this breakthrough.
“We can now illustrate the process in motion, giving us the ability to control it with great precision.”
Professor Alessio Ciulli, Director of CeTPD and a leading authority in the realm of targeted protein degradation, expressed, “This work is incredibly exciting and paves the way for creating more precisely targeted drugs that can finally address diseases that have proven too challenging to treat.”
The Mechanism of Action
Proteins are crucial for the proper functioning of our cells, but when they malfunction, they can lead to disease.
Targeted protein degradation involves manipulating the protein recycling systems in our cells to eliminate proteins responsible for disease.
Protein degraders capture the disease-causing protein, effectively bonding it to the cell’s protein-recycling machinery, which then marks the protein for destruction.
This marking process involves a small protein named ubiquitin, which is delivered to the target protein like a precision shot. For the process to work effectively, ubiquitin must land on the correct sites of the target protein to ensure proper tagging. The latest findings from the Dundee researchers reveal how this ‘shot’ achieves its mark on the target.
The research centered on a protein degrader molecule known as MZ1, developed in the Ciulli lab at Dundee, and employed advanced mass spectrometry to accurately identify where the crucial ‘tags’ are attached to the target protein.
The results demonstrate how degrader drugs effectively secure and position disease-causing proteins, making them suitable candidates for receiving ubiquitin molecules (referred to as “ubiquitin-atable”), which subsequently leads to their degradation within the cell.
The efficiency and effectiveness of protein degradation hinge on the degrader molecule’s capacity to maintain a strong grip on the disease-causing protein, positioning it optimally for action. This recent study creates a stable target, ensuring precise application of the degradation process.
Professor Ciulli noted that this and other recent publications are advancing the swift evolution of this promising scientific domain and drug discovery field.
“This rapidly evolving area of research is captivating. Complementary articles detailing how cellular protein-recycling systems facilitate the targeting of proteins with ubiquitin have recently been published by talented biochemists Brenda Schulman (Max-Planck Institute of Biochemistry) and Gary Kleiger (University of Nevada, Las Vegas).
“Our collective efforts represent a significant leap forward in understanding, which will expedite the development of new TPD drugs in the future.”
