Ubiquitin-Binding Peptides May Have Anti-Cancer Potential

New research out of Technion-Israel Institute of Technology has identified unique peptides that bind to a “death tag” attached to damaged proteins to mark them for disposal. The findings could be used to develop anti-cancer drugs, particularly for patients who have developed resistance to first-line treatments.

Peptides are short chains of amino acids linked by peptide bonds, which are chemical bonds formed between two molecules when the carboxyl group of one molecule reacts with the amino group of the other molecule. Unlike proteins that usually contain hundreds of amino acids, peptides contain, at most, dozens of such acids. 

The cyclic peptides the researchers discovered bind specifically to chains of ubiquitin proteins, mark damaged proteins to be broken down in the proteasome. The discovery of the ubiquitin system led to the awarding of the 2004 Nobel Prize in Chemistry.

Over the years, it has become 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, while linking the ubiquitin at position 63 (K63) leads to the repair of damaged DNA.

 In recent years, Technion researchers have developed a new approach to influencing 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. Work published in 2019 led to cyclic peptides that bind the K48-linked ubiquitin chains, preventing it from leading to the breakdown of the damaged proteins. This disruption gradually leads to programmed death of cells. At the time, the authors hypothesized and then proved that when such an event formed in a malignant tumor, it kills the cancer cells, potentially protecting the patient.

The current study, published in Nature Communications, discovered cyclic peptides that bind the chains linked to position 63 in ubiquitin and that are involved in repairing damaged DNA. 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.

As in the previous work, when this binding occurs in cancer cells, it destroys these cells. The researchers believe this therapeutic strategy could be more effective than existing anti-cancer drugs, against which patients gradually develop a resistance.