New peptides with potential beyond existing anti-cancer drugs

A recent study published in Nature Communications highlights the potential
of unique peptides as anti-cancer agents.
Peptides are short chains of amino acids linked by peptide bonds and have attracted attention
because of their potential role in cancer treatment.

Unlike proteins, which typically contain hundreds of amino acids, peptides contain only a few dozen of these acids
at most.
The cyclic peptide discovered by the researchers binds specifically to the ubiquitin protein chain, which is often used as a "death tag"
for damaged proteins.
The labeling of damaged proteins causes them to be broken down
in the proteasome, the cell's "trash can").

Peptides typically contain no more than a few dozen amino acids, while proteins typically contain hundreds
.
The cyclic peptides recently discovered by the researchers have the ability to specifically bind to ubiquitin protein chains, which are often used as "death tags"
for damaged proteins.
These tagged proteins are then broken down in the proteasome, a cellular structure
responsible for removing waste products.

The study was conducted by Prof.
Ashraf Brik, Dr.
Ganga B.
Vamisetti and Dr.
Abbishek Saha from the Technion's Schulich School of Chemistry, as well as Prof.
Nabieh Ayoub from the Technion's School of Biology and Prof.
Hiroaki Suga from the University of Tokyo
.

The discovery of the ubiquitin system earned three researchers the 2004 Nobel Prize in Chemistry, including Aharon Ciechanover and Avraham Hershko
, distinguished professors at the Ruth Technion and Bruce Rappaport School of Medicine.
Over the years, it has become clear that the activity of the ubiquitin system depends in part on where ubiquitin molecules are connected to each other in the chain
.
For example, linking ubiquitin at position 48 (K48) of the strand causes the protein to be removed to the proteasome, while linking ubiquitin at position 63 (K63) leads to repair of damaged DNA
.

In recent years, Technion researchers have developed a new method
to influence the ubiquitin mechanism.
They decided to try to intervene directly with the ubiquitin chain itself, rather than interfering with the activity
of enzymes that affect these mechanisms.
Based on this approach, the researchers developed cyclic peptides in previous work that bind K48-linked ubiquitin chains, preventing them from leading to the breakdown
of damaged proteins.
This destruction gradually leads to programmed cell death
.
In the same study, they hypothesized and demonstrated that when such an event forms in a malignant tumor, it kills cancer cells, potentially protecting patients
.
The discovery, published in the journal Nature Chemistry in 2019, prompted the formation of a new startup that is pushing the discovery toward clinical applications
.

In the current study, cyclic peptides
that bind to ubiquitin 63-bit chains and are involved in repairing damaged DNA were identified.
The researchers found that when attached to these ubiquitin chains, these peptides disrupt the aforementioned repair mechanisms
.
This leads to the accumulation of damaged DNA and leads to cell death
.
When this binding occurs in cancer cells, it also destroys those cells
.
The researchers believe that this treatment strategy may be more effective than existing anti-cancer drugs, and patients will gradually develop resistance to it
.

1.
Selective macrocyclic peptide modulators of Lys63-linked ubiquitin chains disrupt 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

2.
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