Researchers at the University of Dundee have shown that it is possible to target and destroy specific proteins within cells using a new directed protein missile system. This is very interesting, as it raises the possibility of targeting aberrant proteins present in diseases that currently have no drug that affects them.

This opens the door to treating a range of diseases, as well as potentially being useful in directly targeting proteins involved in the aging process. Before we take a look at the research, let’s recap on why proteins are important, what they do, and how they relate to aging and diseases.

So what are proteins?

Proteins are often called the building blocks of life, and they are critical to the operation of our cells and therefore to our lives. Proteins are produced by the cell and perform a huge variety of functions, such as activating the immune response against pathogens, and regulating metabolism and cellular functions. They do the majority of the work in cells and are required for maintaining the structure, function, and regulation of the body’s tissues and organs.

Proteins are made up of hundreds or even thousands of smaller units called amino acids, which are linked together in long chains. There are twenty different amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique structure and its function. Proteins can be categorized according to their function within the body.







Function Description Antibody Antibodies bind to specific foreign particles, such as viruses and bacteria, as part of the immune response and to help protect the body. Enzyme



Enzymes perform almost all of the thousands of chemical reactions that take place within cells. They also assist with the formation of new molecules by interpreting the genetic information stored in DNA. Messenger Messenger proteins, such as some hormones, transmit signals to coordinate biological processes between the different cells, tissues, and organs. Structural component These proteins provide structure and support for cells. In a larger context, they also allow the body to move.



Transport/storage These proteins bind and carry atoms and small molecules within cells and through the body.

Undruggable proteins

In the majority of diseases, the protein function is altered due to genetic mutation (damage to our DNA) or a deregulated environment where there are too many proteins or too few produced. This change in the function of proteins then causes havoc in the cell and leads to diseases and drives the aging processes too.

During aging, proteins can become misfolded, which leads to protein aggregation and the onset of diseases like Alzheimer’s and Parkinson’s, where damaged proteins build up and destroy brain cells. If these damaged proteins could be targeted effectively, it could potentially be a way to treat neurodegenerative diseases.







Some researchers suggest that only a small number of proteins can actually be targeted by conventional drugs, and the majority of proteins remain untouchable or undruggable. So, being able to target and degrade the proteins in the cell has a vast scope for treating many diseases both age-related and otherwise.

Introducing AdPROM

A research team at Dundee University, led by Dr. Gopal Sapkota has created an Affinity-directed PROtein Missile (AdPROM) system that allows for the precise and rapid targeting and destruction of proteins in the cell. The paper published recently here follows on from earlier work by the same team[1-2].

AdPROM uses small affinity probes, termed nanobodies or monobodies, which bind and recruit target proteins to the cellular protein degradation system to be destroyed.

In a university press release, Dr. Sapkota commented “For the first time we have shown that it is possible to target endogenous proteins for complete degradation with AdPROM,” and “This is extremely exciting and has far-reaching applications and implications for both research and drug discovery. Being able to selectively degrade target proteins in cells rapidly is desirable in research and therapeutics.”







The targeting and rapid destruction of specific proteins could potentially allow scientists to determine the effect of removing these proteins and the possible reversal of disease state by doing so.

The removal of excessive malfunctioning proteins from cells and tissues using AdPROM could be a huge step for medicine but there is much work to be done. Before this technology can be deployed in humans, it would need to pass through the clinical trial process so until then there is much more work ahead for the researchers here. Dr. Sapkota believes that scientific developments in gene delivery techniques could be the way to use AdPROM in the future.

“The AdPROM technology is quite simple to assemble and versatile for use in any cell,” said Dr. Sapkota. “Basically, it requires an affinity probe that selectively recognises the endogenous target protein of choice. With rapid advances in technologies, it won’t be too long before we have access to affinity probes against pretty much every target protein.”

This is true, as technology is advancing rapidly and gene therapy delivery systems are becoming more sophisticated and refined with each passing year.

“This is technology that we can hopefully use to expedite and prioritise drug discovery. Getting a single molecule developed against a target protein costs a lot of money and resources so it is impossible to do this for every protein. AdPROM allows us to manipulate proteins, study their individual functions and find out what happens when they are destroyed. It will allow us to refine the list of targets very, very quickly. Indeed, we are already collaborating with major pharmaceutical companies to streamline drug targets with AdPROM,” Dr. Sapkota concludes.







Conclusion

Should clinical trials pan out, the AdPROM system could be a potent weapon in the fight against all kinds of diseases, including age-related diseases like Alzheimer’s, Parkinson’s, heart disease, and cancer. We wish Dr. Sapkota and his team the best of luck, and we will be watching progress with great interest.

Literature

[1] Fulcher, L. J., Hutchinson, L. D., Macartney, T. J., Turnbull, C., & Sapkota, G. P. (2017). Targeting endogenous proteins for degradation through the affinity-directed protein missile system. Open Biology, 7(5), 170066.

[2] Fulcher, L. J., Macartney, T., Bozatzi, P., Hornberger, A., Rojas-Fernandez, A., & Sapkota, G. P. (2016). An affinity-directed protein missile system for targeted proteolysis. Open Biology, 6(10), 160255.





