Health, UK (Commonwealth Union) – A groundbreaking discovery made by scientists at the University of Dundee holds promise for advancing drug development in tackling cancers and neurodegenerative diseases.
Led by Professor Alessio Ciulli at the Centre for Targeted Protein Degradation (CeTPD), in collaboration with Dr. Georg Winter’s team at the Research Center for Molecular Medicine (CEMM) of the Austrian Academy of Sciences in Vienna, the researchers have identified a novel category of molecular glue known as “intramolecular bivalent glue.” These compounds have the ability to bind proteins crucial for cellular functions, which would otherwise remain unbound.
Published in the journal Nature, this research marks a significant step forward in the quest for more effective treatments against various diseases.
Professor Alessio Ciulli, Director of Dundee’s CeTPD, emphasized the significant ramifications of these discoveries for the broader pharmaceutical sector focused on targeted protein degradation.
Professor Ciulli, further indicated that these findings hold profound significance, especially in the realm of drug development for conditions such as cancer, neurodegenerative diseases, and numerous other ailments driven by traditionally deemed ‘undruggable’ proteins.
“Proteins are essential for our cells to function properly, but when these do not work correctly the body is vulnerable to disease.
“The glue that we have been able to define is special because it first attaches itself to one protein in two places – not just one – and then recruits the second protein, effectively sandwiching the two proteins together.
Professor Ciulli pointed out that this was possible utilizing our Targeted Protein Degradation (TPD) technology, where they have uncovered a vulnerability with profound implications for cancer treatment and other challenging diseases. This advancement opens the door to designing novel drugs that could revolutionize patient care.
TPD is a cutting-edge approach in drug development, leveraging cellular protein recycling systems to eliminate disease-causing proteins. Typically, this involves utilizing small molecules, known as degraders, to engage target proteins with ubiquitin E3 ligases. These ligases tag the target proteins with ubiquitin labels, leading to their degradation via the proteasome.
In collaboration with partners from CEMM, Goethe University of Frankfurt, and Eisai Co. Ltd, the Dundee team has uncovered a unique molecular glueing mechanism. Unlike previously identified mechanisms, this novel approach binds to both sides of the target protein, inducing a significant protein rearrangement and stabilizing its previously unknown interaction with the E3 ligase.
Moreover, the team achieved a breakthrough by visualizing, for the first time, the precise mechanism through which their compounds operate and bring together the target proteins to one of these E3 ligases. Due to the molecules possessing two heads, which attach to two distinct regions within the same target protein, they have been termed intramolecular bivalent glues.
Researchers of the study pointed out that this pioneering research has also shed light on previously overlooked characteristics and attributes of molecular glues, laying the groundwork for scientists to gain a deeper comprehension of glues that could expedite the discovery of new classes.
Professor Ciulli emphasized that the significance of their findings here could not be overstated.
“This will cause a ripple effect throughout the pharmaceutical industry and has the potential to transform how we view drug development.
“Dundee is a world-leader in TPD, and our new home here at the Centre for Targeted Protein Degradation will only further enhance the reputation of the University in this revolutionary space.
“I must also pay tribute to our collaborators, whose input has been crucial in achieving this seismic breakthrough.”
Professor Ciulli, hailing from the University’s School of Life Sciences, stands at the forefront of advancing understanding in TPD. Collaborating with his team, he has pioneered degrader molecules that are now deployed worldwide in the pursuit of innovative therapies for ailments including cancer, dermatological issues, and neurological disorders. The field of TPD research has garnered substantial global investment, with Dundee earning widespread acclaim as a premier hub in this domain.
TPD represents a groundbreaking approach with the potential to unlock therapeutic avenues previously deemed inaccessible. By harnessing the cell’s natural protein degradation machinery, TPD offers a highly precise and potent method for eliminating disease-causing proteins within cells. As research progresses and technologies evolve, TPD holds the promise of delivering transformative therapies across various disease indications, paving the way for a new era in drug discovery and development.
