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Shen, Fangfang., Dassama, Laura M.K., Opportunities and challenges of protein-based targeted protein degradation, Royal Society of Chemistry, https://pubs.rsc.org/en/content/articlelanding/2023/sc/d3sc02361c#!divAbstract
For the past 20 years, researchers have been using a technique called targeted protein degradation to break down certain proteins to treat disease. In the past, targeted protein degradation was very limited because only molecules that were smaller in size were able to be used and as a result, the protein degradation was only effective in certain parts of the cell. Recently, however, there have been new advancements to targeted protein degradation such as the use of proteins and nucleic acids (which make up DNA) to degrade proteins in areas that were much harder to reach in the past.
To understand targeted protein degradation, it is important to know how it works. In cells, there are 2 primary ways that materials like proteins are broken down: through a lysosomal pathway or through a proteasomal pathway.
In the lysosomal pathway, materials both inside and outside of the cell are broken down by parts of the cell called lysosomes, which function as the trash cans of the cell. Inside of lysosomes are enzymes, which are proteins meant to speed up chemical processes. When materials like proteins enter the cell, they are transported to these lysosomes where they are broken down with the help of the enzymes. The cell is then able to reuse or recycle its old parts that were broken down and repurposed by the lysosomes.
The second type of protein degradation is the proteasomal pathway. Proteasomes are complexes formed by enzymes which function to cut up proteins. In order for the cell to know which proteins to break down, the proteins must be tagged. In proteasomal pathways, a protein called ‘ubiquitin’ marks each of the proteins for degradation, which sends the “okay signal” for the enzymes to break down the proteins.
One new type of targeted protein degradation is called AbTACs, which uses antibodies (molecules that fight disease) that are able to target more than one type of disease or problem in the cells. Using these antibodies, an enzyme called ligase is able to be brought to the target proteins and consequently, the proteins are broken down. In another connected study on antibodies in targeted protein degradation, researchers discovered that the use of specific multi-functional antibodies was able to degrade an insulin growth factor, which controls growth hormones in the body. This finding is exciting because if growth hormones can be controlled more effectively in the human body, then cancer cells will no longer be spurred to continue multiplying and creating more cancer.
However, one current limitation to this type of targeted protein degradation is the specificity required for the antibodies. Average antibodies are unable to function properly for the purpose of protein degradation because the antibodies must be bi-specific, meaning able to target more than one disease. In order for the antibodies to be as specific as possible, the structure of the antibody must be very precise and the design of the shape must be carefully done.
In the future, it is likely that we will find more studies such as this one on targeted protein degradation because the concept has been researched for over 2 decades now, but most recently, new developments have been made which could have incredible implications for diseases such as cancer. In biomedicine, targeted protein degradation is often used as a therapy to treat disease, which makes sense because certain protein differences can cause imbalance issues within the body, increasing the chances of disease.
By Jeannine Yu
References:
“Antibody.” Genome.Gov, www.genome.gov/genetics-glossary/Antibody. Accessed 24 Aug. 2023.
“Bispecific Antibody.” Amgen, www.amgen.com/stories/2018/08/the-shape-of-drugs-to-come/bispecific-antibody#:~:text=Bispecific%20antibodies%20aim%20to%20treat,specifically%20target%20a%20single%20antigen. Accessed 24 Aug. 2023.
“Insulin-like Growth Factor.” Insulin-Like Growth Factor - Health Encyclopedia - University of Rochester Medical Center, www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=167&ContentID=insulin_like_growth_factor#:~:text=IGF%2D1%20is%20a%20hormone,of%20GH%20in%20the%20blood. Accessed 24 Aug. 2023.
“Ligase.” Ligase - an Overview | ScienceDirect Topics, www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/ligase. Accessed 24 Aug. 2023.
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