Proteins perform a wide range of cellular functions and most drugs target proteins, preventing them from functioning and therefore inhibiting whatever outcome they help achieve. However, developing single molecules that can travel through the bloodstream to the target, enter the cell, and bind to the correct molecule is challenging. Additionally, by repressing a specific protein, cells may end up producing more of it over time in order to counteract the lack of desired outcome. This typically requires increased drug dosages to address.
One solution to the challenge of developing these multi-functional drugs is the “proteolysis-targeting chimera,” or PROTAC- molecules that place tags on desired proteins so that, instead of being silenced, the protein is broken down by the proteasome, the cell’s protein garbage disposal. While the PROTAC is able to target a wide variety of proteins inside the cell, a major limitation of the PROTAC system is its inability to target proteins found on the cell surface. Since these types of molecules are essential for cell communication and are overactive in cancer, it’s important that the system also regulates these proteins. Now, Dr. Banik, Dr. Bertozzi, and colleagues from Stanford University have developed the lysosomal targeting chimera, or LYTAC, which works similarly to the PROTAC, but is designed to target these surface proteins. This system works similarly but uses a different cellular system as its target, allowing cell surface proteins to be digested as well.
After optimizing the synthesis and properties of the LYTAC, the authors turned to three examples of important cellular targets. The first, EGFR, is a well-known cancer target and can serve important roles in metastasis even if its normal function is inhibited by drugs. By exposing cells expressing EGFR to LYTACs, over 70% of the molecules were degraded after 24 hours, and degradation persisted up to 72 hours. These results were confirmed in cell lines derived from liver and breast cancer tissues, which are known to express this protein. Similar results were found in LYTACs targeting CD-71, a relatively new cancer target, and PD-L1, a protein which helps cancer cells avoid detection by the immune system.
These initial results are quite promising, but challenges remain. The question of clearance is essential- how quickly do these LYTACs exit the body once they are inside? Highly efficacious molecules that are quickly cleared by the liver or kidneys have little therapeutic benefit. Blood from mice exposed to LYTACs showed a rapid clearance phase over the first six hours followed by a slower phase over the next few days. This can differ for LYTACs targeting different proteins, so it will need to be further studied. Drugs targeting pathways found in all cells may have off-target effects, causing destruction of a protein similar to the target or of the target protein in healthy tissue. Increasing specificity of delivery or activity of the LYTAC could help avoid these side effects, though this is a problem for other drugs also. Lastly, it remains to be seen if utilizing degradation instead of silencing will prevent cells from increasing their protein production over time, necessitating higher doses. Overall, the development of LYTACs represents an important step forward in the design of a new, better generation of modular therapeutics.
Steven M. Banik is a postdoctoral researcher in the Bertozzi Group at Stanford University. Dr. Carolyn R. Bertozzi is the Anne T. and Robert M. Bass Professor of Chemistry and Professor of Chemical Systems Biology and Radiology at Stanford University and is the Principal Investigator of the Bertozzi Group.
Managing Correspondent: Andrew T. Sullivan
Press Articles: “Chemists craft molecular scalpels to clear unwanted proteins from cell surfaces,” phys.org
Original Journal Article: “Lysosome-targeting chimaeras for degradation of extracellular proteins,” Nature
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