New Israeli-Japanese-American strategy could help eliminate cancer cells

The study, which was published recently in “Nature Chemistry,” is considered a milestone in the application of the discovery of the ubiquitin system.

Prof. Ashraf Brik (photo credit: TECHNION SPOKESPERSON'S OFFICE)
Prof. Ashraf Brik
An innovative strategy for eliminating cancer cells has been developed by an international team led by Israel’s Technion.
The study, which was published recently in Nature Chemistry, is considered a milestone in the application of the discovery of the ubiquitin system. Israeli researchers Avram Hershko and Aaron Ciechanover, and US biologist Irwin Rose, won the 2004 Nobel Prize in Chemistry for studying the roles of the ubiquitin system in controlling the cell division process, which today is playing a key role in understanding and curing certain types of cancer.
While many research groups around the world have been working on the ubiquitin system and harnessing it for developing innovative medical treatments – including discovering four drugs approved for treatments – “the progress in the study of the ubiquitin system and the development of drugs based on its understanding are very slow relative to its potential,” said Prof. Ashraf Brik of the Schulich Faculty of Chemistry at the Technion-Israel Institute of Technology, who headed the recent study.
The strategy developed by Brik and colleagues from Japan and America neutralizes the ability of the malignancy to perform the same manipulation. It is based on an unprecedented combination of Brik’s skill in producing ubiquitin chains using advanced chemical methods and Prof. Hiro Suga of the University of Tokyo’s method of creating very large libraries of molecules called cyclic peptides. As part of the collaboration, the researchers discovered how these cyclic peptides bind to the ubiquitin chains and thus inhibit the breakdown of proteins that help the cancer to grow and thrive.
“We use total chemical synthesis of proteins to generate highly homogeneous Ub chains for screening against trillion-member macrocyclic peptide libraries,” the researchers explain in a medical abstract. “De novo cyclic peptides were found that can bind tightly and specifically to K48-linked Ub chains, confirmed by NMR studies. These cyclic peptides protected K48-linked Ub chains from deubiquitinating enzymes and prevented proteasomal degradation of Ub-tagged proteins. The cyclic peptides could enter cells, inhibit growth and induce programmed cell death, opening new opportunities for therapeutic intervention.”
In other words, this highly synthetic approach, with both protein target generation and cyclic peptide discovery performed in vitro, will make other elaborate post-translationally modified targets accessible for drug discovery and pave the way for new types of anticancer treatments, according to a release by the Technion.
Ub refers to ubiquitination (the covalent conjugation of ubiquitin to other cellular proteins), which regulates a wide range of cellular processes. Often, multiple Ub molecules are added to the substrate to form a Ub chain.
The other researchers involved in the project include Nobel winner Ciechanover of the Technion’s Rappaport Faculty of Medicine, and Prof. David Fushman of the University of Maryland’s Department of Chemistry and Biochemistry.