The research study was performed by Professor Ashraf Brik, Dr. Ganga B. Vamisetti, and Dr. Abbishek Saha from the Schulich Faculty of Chemistry at the Technion– Israel Institute of Technology, in addition to Professor Nabieh Ayoub from the Technions Faculty of Biology and Professor Hiroaki Suga from the University of Tokyo..
The discovery of the ubiquitin system led to the awarding of the 2004 Nobel Prize in Chemistry to three researchers, consisting of Distinguished Professors Aharon Ciechanover and Avraham Hershko of the Technions Ruth and Bruce Rappaport Faculty of Medicine.
For many years, it ended up being clear that the activity of the ubiquitin system depends in part on the point where the ubiquitin particles are connected to each other in the chain. For instance, connecting the ubiquitin in the chain at position 48 (K48) causes the elimination of proteins to the proteasome, while linking the ubiquitin at position 63 (K63) leads to the repair work of damaged DNA.
Recently, Technion scientists have actually established a brand-new method to affecting the ubiquitin systems. Rather of interfering with the activity of enzymes that affect these systems, they chose to try to directly intervene in the ubiquitin chain itself.
Based on this technique, the researchers in a previous work established cyclic peptides that bind the K48-linked ubiquitin chains, avoiding them from leading to the breakdown of the broken proteins. This discovery, released in 2019 in the journal Nature Chemistry, led to the establishment of a brand-new startup that is advancing the discovery toward medical use.
In the current study, cyclic peptides that bind the chains connected to place 63 in ubiquitin which are associated with repairing broken DNA were found. The researchers found that when attached to these ubiquitin chains, such peptides interrupt the aforementioned repair mechanism. This causes the accumulation of broken DNA, and to cell death. Here too, when this binding happens in cancer cells, it destroys these cells. The scientists believe this restorative method could be more efficient than existing anti-cancer drugs, against which clients gradually develop resistance.
References: “Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains interrupt DNA damage repair” by Ganga B. Vamisetti, Abhishek Saha, Yichao J. Huang, Rajeshwer Vanjari, Guy Mann, Julia Gutbrod, Nabieh Ayoub, Hiroaki Suga and Ashraf Brik, 18 October 2022, Nature Communications. DOI: 10.1038/ s41467-022-33808-6.
” De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains” by Mickal Nawatha, Joseph M. Rogers, Steven M. Bonn, Ido Livneh, Betsegaw Lemma, Sachitanand M. Mali, Ganga B. Vamisetti, Hao Sun, Beatrice Bercovich, Yichao Huang, Aaron Ciechanover, David Fushman, Hiroaki Suga and Ashraf Brik, 10 June 2019, Nature Chemistry.DOI: 10.1038/ s41557-019-0278-x.
The scientists believe that the brand-new method could be more effective than existing cancer drugs.
Researchers from the Technion and the University of Tokyo have recognized special peptides with potential anti-cancer residential or commercial properties.
A research study just recently published in Nature Communications highlights the capacity of special peptides as anti-cancer agents. Peptides, which are brief chains of amino acids connected by peptide bonds, have garnered attention for their potential role in cancer treatment.
Unlike proteins that generally include numerous amino acids, peptides contain– at most– lots of such acids. The cyclic peptides the researchers found bind particularly to chains of ubiquitin proteins– proteins that are generally utilized as a “death tag” for broken proteins. The labeling of the damaged proteins leads to their being broken down in the proteasome, or the cells “trash bin.”
Peptides normally include no greater than a couple of dozen amino acids, in contrast to proteins which usually contain hundreds. The cyclic peptides just recently discovered by researchers have the ability to bind particularly to chains of ubiquitin proteins, which are typically utilized as a “death tag” for broken proteins. These marked proteins are then broken down in the proteasome, a cellular structure accountable for getting rid of waste.
The cyclic peptides the scientists discovered bind specifically to chains of ubiquitin proteins– proteins that are typically used as a “death tag” for damaged proteins. The cyclic peptides just recently discovered by researchers have the capability to bind specifically to chains of ubiquitin proteins, which are typically used as a “death tag” for damaged proteins. Based on this approach, the researchers in a previous work established cyclic peptides that bind the K48-linked ubiquitin chains, preventing them from leading to the breakdown of the broken proteins. In the present study, cyclic peptides that bind the chains connected to place 63 in ubiquitin and that are included in fixing broken DNA were found. The researchers discovered that when connected to these ubiquitin chains, such peptides interrupt the previously mentioned repair mechanism.
