De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains


Since “the discovery of ubiquitin-mediated protein degradation” which awarded Ciechanover, Hershko and Rose the Nobel Prize in Chemistry for 2004, scientists are trying to translate the gained knowledge in this system into real medicines that improves the lives of many patients. Indeed, there are currently four approved drugs in the market that work on the ubiquitin system, which are used for cancer in particular in multiple myeloma. Despite these successes and the huge potential in targeting the hundreds of enzymes involved in the ubiquitin system, progress in this this area is relatively slow compared to other systems such as in kinases. Therefore, new approaches that target different components in this system are extremely important, which could open new opportunities in drug development. In a new study that was published recently in Nature Chemistry, led by Professor Ashraf Brik from the Schulich Faculty of Chemistry in collaboration with Professor Aaron Ciechanover, Professor David Fushman (Maryland University) and Professor Hiro Suga (Tokyo University), the team reported on a novel targeting approach that is underexplored in this field. The new strategy combines the power of the Brik’s approach to chemically prepare ubiquitin chains and the Suga’s method to generate large libraries (1012 !) of cyclic peptides from which the team found strong binders to ubiquitin chains. The team was able to characterize how these cyclic peptides bind to the chains and the biological effects on cellular protein degradation. As a result, cancer cells, which are extremely sensitive to interference of the ubiquitin system, undergo apoptosis making these cyclic peptides of therapeutic potential.  The approach promises new studies for understanding the complexity of the ubiquitin system with potential development of new drugs.


Figure: The combined strategy of using synthetically Ub chain and large library of cyclic peptides to select for strong binders against the different chains.

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