A team led by University of Dundee researchers has identified a new class of molecular glue that could pave the way for a new generation of drugs to target cancers and neurodegenerative diseases.
“These findings have major implications for the entire pharmaceutical industry engaged in targeted protein degraders,” said Professor Alessio Ciulli senior author of the paper published in Nature.
The newly discovered intramolecular bivalent glue works by first attaching itself to one protein in two places—not just one—and then recruiting the second protein, effectively sandwiching the two proteins together.
This mechanism not only binds to two sides of a target protein, prompting a rearrangement that stabilizes its interaction with ubiquitin E3 ligases but also marks the protein for destruction by the cell's waste disposal system, the proteasome.
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In addition, the team was able to visualize the precise mechanism by which their compounds work and bring together the target proteins to one of these E3 ligases. Because the molecules have two heads, which latch on to two different regions within the same target protein, these have been coined intramolecular bivalent glues.
This work sheds light on previously unknown aspects of molecular glues, offering insights that could accelerate the discovery of new drug classes. According to Professor Ciulli, “This will cause a ripple effect throughout the pharmaceutical industry and has the potential to transform how we view drug development.