Peptides are short chains of amino acids linked by peptide bonds, the name given to chemical bonds formed between two molecules when the carboxyl group – a combination of two functional groups attached to a single carbon atom – of one molecule reacts with the amino group of the other molecule.
A new Israeli/Japanese study just published in the prestigious peer-reviewed journal Nature Communications presents research on unique peptides with anti-cancer potential. It was published under the title “Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt DNA damage repair.”
The researchers believe this therapeutic strategy could be more effective than existing anti-cancer drugs that patients gradually develop a resistance to.
Who was the research led by?
The research was led by Prof. Ashraf Brik and postdoctoral fellows Dr. Ganga B. Vamisetti and Dr. Abbishek Saha from the Schulich Faculty of Chemistry at the Technion-Israel Institute of Technology in Haifa, along with Prof. Nabieh Ayoub from the Technion’s Faculty of Biology and Prof. Hiroaki Suga from the University of Tokyo.
Unlike proteins that usually contain hundreds of amino acids, peptides contain, at most, just a few dozen. The cyclic peptides the researchers discovered bind specifically to chains of ubiquitin proteins, which usually are used as a “death tag” for damaged proteins. The labeling of the damaged proteins leads to their being broken down in the proteasome, which is the cell’s “garbage can.”
The discovery of the ubiquitin system led to the awarding of the 2004 Nobel Prize in Chemistry to three researchers, including distinguished professors Aharon Ciechanover and Avraham Hershko of the Technion’s Rappaport Faculty of Medicine.
Over the years, it became clear that the activity of the ubiquitin system depends in part on the point where the ubiquitin molecules are linked to each other in the chain. For example, linking the ubiquitin in the chain at position 48 (K48) leads to the removal of proteins to the proteasome protein complexes, which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Linking the ubiquitin at position 63 (K63) leads to the repair of damaged DNA. Enzymes that help such reactions are called proteases.
In recent years, Technion researchers have developed a new approach to influencing the ubiquitin mechanisms. Instead of interfering with the activity of enzymes that affect these mechanisms, they decided to try to directly intervene in the ubiquitin chain itself.
Based on this approach, the researchers in a previous work developed cyclic peptides that bind the K48-linked ubiquitin chains, preventing them from leading to the breakdown of the damaged proteins. This disruption gradually leads to the programmed death of cells.
In the same study, they hypothesized and then proved that when such an event formed in a malignant tumor, it kills the cancer cells, potentially protecting the patient. This discovery, published in 2019 in the peer-reviewed journal Nature Chemistry, led to the establishment of a new start-up that is advancing the discovery toward clinical use.
In the current study, cyclic peptides that bind the chains linked to position 63 in ubiquitin and that are involved in repairing damaged DNA were discovered. The researchers found that when attached to these ubiquitin chains, such peptides disrupt the aforementioned repair mechanism. This leads to the accumulation of damaged DNA and to cell death. Here, too, when this binding occurs in cancer cells, it destroys them.