Recent advancements in molecular science could hold the key to treating a range of diseases that have been previously deemed ‘undruggable.’ These include various forms of cancer and neurodegenerative conditions. Scientists at the University of Dundee have made a breakthrough by unveiling the operations of molecules known as ‘protein degraders’ in unprecedented detail.
Protein degraders have sparked a paradigm shift in drug discovery, with over 50 such substances currently undergoing clinical trials for patients with diseases that lack alternative treatment options. The University of Dundee’s Centre for Targeted Protein Degradation (CeTPD) is a global pioneer in researching the functionality of protein degraders and their potential in developing a new class of drugs.
The team at Dundee has now revealed more about how these intriguing molecules operate. Their findings offer a deeper understanding of protein degraders, enabling a more precise application at the molecular level.
Charlotte Crowe, a PhD student, and Dr Mark Nakasone, a Senior Postdoctoral Scientist at CeTPD, utilized cryo-electron microscopy (cryo-EM). This technology allows scientists to observe the movement and interaction of biomolecules by flash-freezing proteins and generating millions of 2D images using an electron beam and a high-resolution camera. Advanced software and AI models were then used to create 3D visuals of the protein degrader drugs in action.
Their groundbreaking research, published in Science Advances, provides a significant contribution to the field of Targeted Protein Degradation (TPD) and ubiquitin mechanisms.
Charlotte Crowe explains how this research aids in understanding the working of protein degraders at a molecular level. She likens the process to targeting a bull’s eye, now visible thanks to their research.
The protein degraders function differently from conventional drugs, capturing disease-causing proteins and sticking them to the cellular protein-recycling machinery. This machinery then marks the protein for destruction. The marking process involves a small protein known as ubiquitin, which is figuratively shot at the disease-causing protein. To be effective, the ubiquitin must hit specific spots on the target protein for successful tagging.
The Dundee team, working with a protein degrader molecule named MZ1, developed in the Ciulli laboratory at Dundee, used sophisticated mass spectrometry to identify where these crucial tags are added on the target protein.
This research helps understand how degrader drugs latch onto and position disease-causing proteins, making them prime targets for receiving ubiquitin molecules, which then leads to their destruction within the cell.
Professor Alessio Ciulli, Director of CeTPD, is enthusiastic about the future of this rapidly expanding field of science and drug discovery. He believes this collective research will expedite the development of new TPD drugs in the future.
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