As we hunt for newer ways to treat health issues, our search is increasingly turning inward. Advances in technology have helped us understand (and harness) the body’s built-in mechanisms to deal with invaders, rogue cells and now a cell’s natural process of cleaning up junk.
Researchers are trying to harness this natural process by which cells clean up unwanted and damaged proteins. They are hoping to develop innovative approaches to fight blood cancers and other conditions that are caused by single genetic mutations.
Understanding proteins
Think of proteins as essential workers in our cells. They are responsible for nearly all tasks within cells – maintaining their shape, organising its components, manufacturing necessary materials, and removing waste, apart from receiving external signals to mobilise a response.
But proteins can also disrupt the normal functioning of cells, either due to their presence in excess or because of damage to some of them. Cells have, however, developed ways to regulate their protein levels and keep things in check.
One way cells do this is by tagging damaged and unwanted proteins with a molecule called ubiquitin. These tagged proteins are then sent to a part of the cell known as the proteasome where they are broken down into smaller pieces that can be reused. Proteasomes act as the cell’s recycling centre.
Scientists noticed this natural cleanup process and recreated something similar, called proteolysis-targeting chimaeras or PROTACs in short. These special molecules take advantage of the cell’s internal mechanism to break down proteins. Leveraging them could offer a new way to treat health conditions.
“PROTAC therapy represents a completely new class of drugs,” says Dr. Attili Venkata Satya Suresh, a medical oncologist and haematologist at Continental Hospitals in Hyderabad. “Unlike traditional methods like tyrosine kinase inhibitors or monoclonal antibodies, PROTAC works by breaking down specific amino acids to disrupt pathways.”
Tyrosine kinase inhibitors are a class of medicines that inhibits enzymes responsible for the activation of several types of proteins and are largely used in the treatment of cancers. In contrast, monoclonal antibodies are used to stimulate the immune system to attack cancer cells.
Treatment for leukaemia
Building on this technology, researchers at the Southern University of Science and Technology in Shenzhen, China focused on a protein named BCR-ABL that is formed due to a genetic irregularity called the Philadelphia chromosome translocation, which fuels leukaemia development.
Current treatments for chronic myeloid leukaemia (CML) can become less effective as cells find new ways to grow. However, PROTACs could offer a solution as they can swiftly break down the problem proteins, potentially making treatments more effective.
To do this, the scientists attached small molecules called amino acids (like arginine, lysine, leucine, and phenylalanine) to a molecule that targets BCR-ABL. These amino acids act as signals, telling the cell to break down the faulty protein.
But then they hit a wall. Only a few of the E3 ligases (a special protein inside cells that tags other proteins to signal the cell’s machinery to break them down) could be used with PROTACs and the size of the PROTACs itself restricted their entry into cells. Controlling the rate of protein breakdown also posed a challenge.
To overcome this, they examined another pathway (N-end rule). They attached single amino acids to a molecule targeting the BCR-ABL protein in leukaemia and activated an E3 ligase named UBR1 that broke down the harmful material.
In their lab tests, they demonstrated that these PROTACs effectively broke down the BCR-ABL protein and halted cancer cell growth. A PROTAC containing arginine worked exceptionally well in mice with leukaemia, reducing the effect of the ailment.
The choice of amino acid matters because the E3 ligase can only recognise specific sequences of amino acids. This recognition is based on how atoms and functional groups are arranged within the amino acid’s structure. Thus, it is the arrangement of amino acids that allows them to act as signals for the degradation process.
“PROTACs could effectively target cancers with known oncogenic mutations that can interact with both a ligand and a specific E3 ligase. This approach holds promise for treating such cancers by breaking down the problematic proteins at their root cause,” explains Dr Rama Krishna, Director, Osmania University, Hyderabad.
Challenges PROTACs face
However, while this technology is extremely promising, it may be limited to only treating health issues caused by a single genetic mutation, explains Dr. Suresh. Concerns about unintended toxicity, the need for specific inhibitors and the evolving nature of the field also exist, Dr Krishna points out.
“While PROTAC technology shows promise for single-gene mutation-driven conditions like leukaemia, it faces significant challenges when dealing with solid tumours,” says Dr Suresh. The heterogeneity of solid tumours and their ability to develop resistance by switching on/off pathways make targeting them more complex.
Developing effective PROTACs requires various skills and poses challenges from a chemistry perspective. Nevertheless, new technologies such as silico modelling are on the horizon that could simplify this complexity, the experts add.
