Step-by-Step walkthrough of targeted protein degradation: Understanding the science and impact

Contributors : Nishanth Kandepedu
Date : Apr’25

Introduction

Protein degradation is an important process in the cell. It helps keep the cell healthy and functioning properly. Targeted protein degradation (TPD) is a new treatment that uses this process to eliminate harmful proteins related to diseases. Instead of only stopping a protein’s function, TPD focuses on completely removing it from the cell. This gives a powerful new approach to finding and developing drugs.

Understanding Targeted Protein Degradation

TPD changes the way proteins are balanced in cells. It guides the cell’s system that breaks down proteins to focus on specific proteins we want to treat. Small molecules assist in this process by moving the target protein closer to the cell’s tools for breaking proteins down.

What makes TPD special is that it can pay attention to more proteins than older methods, which just block them. This new way helps us discover treatments for diseases linked to proteins we couldn’t reach before. These proteins include key ones like transcription factors and scaffolding proteins.

The Basics of Protein Degradation

The human body has smart ways to break down proteins and recycle them. This process helps keep our cells healthy. There are two main systems that do this work. They are the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP).

The UPS tags proteins using molecules known as ubiquitin. These tags inform the proteasome, a part of the cell, to locate and break down the identified protein.

The ALP works in a unique way. It takes in proteins through autophagosomes, which are sacs made of two membrane layers. These sacs then join with lysosomes. When they come together, enzymes in the lysosomes break down the proteins inside. Many targeted protein degradation (TPD) methods aim to control either the UPS or the ALP. This focus is to break down certain proteins.

Importance in Disease Treatment and Prevention

Targeted protein degradation might change how we treat and prevent diseases. Rather than just blocking harmful proteins, this method eliminates them entirely. This makes it a powerful choice for challenging issues that regular treatments can’t help with.

TPD helps by removing proteins that are linked to several health issues. These issues include cancer, immune problems, and brain diseases. This makes TPD a strong option for making new medicines. TPD might also perform better than regular small-molecule drugs. This could help us avoid unwanted side effects.

TPD uses a special method where one molecule can attach to many harmful proteins that need to be removed. This makes it work better and could let us use smaller doses than regular treatments. As TPD research grows, it may significantly help health by creating new ways to treat several types of diseases.

Historical Perspective on Protein Degradation

Targeted protein degradation might seem like a fresh concept, but it really started a long time ago. In the 1970s and 1980s, we discovered the ubiquitin-proteasome system (UPS). This was key to understanding how our cells break down proteins. It allowed scientists to explore how this knowledge could be used in treatments.

• Early results about the UPS show it helps maintain the right levels of proteins in cells.
• They also hint that this system could lead to new treatments.
• These advances are the first steps to creating targeted protein degraders.

Mechanisms of Targeted Protein Degradation

Targeted protein degradation focuses on using the cell’s natural systems to break down proteins. These systems are the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). They are important for keeping protein homeostasis. They help balance proteins in our cells and can be adjusted to remove specific target proteins.

Scientists can create small molecule degraders that help break down harmful proteins in the body. This offers a new method to treat various diseases.

Ubiquitin-Proteasome System (UPS)

The ubiquitin-proteasome system (UPS) is key for breaking down certain proteins in the cell. It tags these proteins with a molecule called ubiquitin. This is done by enzymes known as ubiquitin ligases. After tagging, the proteins undergo further breakdown by the proteasome. This process helps keep protein levels balanced in the cell. By understanding how the UPS works, researchers are finding new ways to target protein degradation.

Autophagy-Lysosome Pathway (ALP)

The autophagy-lysosome pathway (ALP) is very important for keeping the cell healthy. It helps break down damaged parts and unwanted proteins using lysosomes. ALP works together with the ubiquitin-proteasome system (UPS) to remove unneeded or misfolded proteins. Recent advances show how ALP and UPS work together to manage protein changes and keep cells in good shape. This knowledge opens new chances for treating diseases like cancer and neurodegenerative disorders.

Key Technologies in Targeted Protein Degradation

New technologies have been developed for targeted protein degradation. They use the cell’s natural methods to get rid of specific proteins. These technologies mainly concentrate on two systems: the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). They help break down proteins connected to diseases. Let’s see what those technologies are –

PROTACs – Proteolysis Targeting Chimeras

PROTACs, or proteolysis-targeting chimeras, are unique molecules. They are made of two connected parts. One part binds to the target protein, while the other links to an E3 ubiquitin ligase. This practice helps PROTACs bring the target protein near the E3 ligase. This closeness allows the creation of the PROTAC-target protein-E3 ternary complex. Then, this process leads to the ubiquitination and degradation of the target protein.

People are really interested in PROTACs. They see them as a useful tool for Targeted Protein Degradation (TPD). PROTACs can break down different types of proteins. This includes proteins that are tough to target with regular small molecule drugs. The design of PROTACs is flexible. Researchers can easily change the binding parts to specifically target certain proteins.

One PROTAC molecule can break down several target proteins. This makes them very strong. It may allow for smaller doses than normal inhibitors. This stronger effect can help make treatments better while lowering side effects.

Molecular Glues

Molecular glues are not the same as PROTACs. They do not directly connect the target protein to the E3 ligase. Instead, they bind to the E3 ligase by itself. This binding causes changes that alter what the ligase targets. When molecular glues attach to a certain E3 ligase, they form new connections with proteins known as neo-substrates. These proteins are typically not recognized by the ligase in normal body functions.

Molecular glues can focus on proteins that lack clear binding sites. This means more proteins can be impacted by targeted protein degradation (TPD). Also, molecular glues are usually smaller than PROTACs. Their smaller size might help them move more easily through cells, which is important for the effectiveness of the drugs.

Discovering and creating molecular glues gives us new ways to target hard-to-reach proteins in treatment. Researchers are looking for and examining new molecular glues. These compounds can help destroy disease-causing proteins linked to several health problems.

Hydrophobic Tags

Hydrophobic tags provide a new way to target and break down bad proteins. They use the cell’s natural systems that deal with proteins that are misshapen or damaged. This method adds a small, hydrophobic part to the protein we want to focus on.

The cell’s chaperone proteins see the hydrophobic part of the tagged protein. Chaperones help in folding proteins and ensure they are dealt with properly. They guide the tagged proteins to the pathways that break them down, mostly through the proteasome.

Hydrophobic tags may not be as well-known as PROTACs or molecular glues, but they have their own unique benefits. They can target and break down proteins outside the cell. However, there are challenges to overcome. We need to ensure that we only focus on specific proteins without harming others. More research and development are needed to solve these problems.

LYTACs – Lysosome Targeting Chimeras

LYTACs are unique molecules that function like PROTACs. They focus on specific proteins and help in breaking them down. Rather than using the regular way that involves the ubiquitin-proteasome system, LYTACs take a different approach. They use the autophagy-lysosome pathway instead. This pathway helps to break down large protein clusters and damaged parts of cells.

A typical LYTAC has two parts. One part sticks to the target protein we want to break down. The other part connects to a receptor on the cell surface of the lysosome. When the LYTAC attaches to the target protein, it forms a complex. This complex is then taken in by small bubbles called autophagosomes. These bubbles merge with lysosomes. Inside the lysosome, an acidic environment and special enzymes break down the target protein.

LYTAC technology creates new options in targeted protein degradation (TPD). It can access proteins that the proteasome cannot reach. This includes proteins outside of cells and those that are caught in cell membranes. This method might be very useful for treating diseases that do not respond to small molecule drugs.

Advancements in Drug Discovery through TPD

Targeted protein degradation is transforming drug discovery. It offers a powerful way to tackle diseases that seemed tough to treat. This approach opens up new opportunities for making drugs. It allows us to target more types of proteins, going beyond what small molecule inhibitors could achieve.

This big change is quickly transforming medicine. It gives hope for finding helpful treatments for many diseases. These include cancer, immune disorders, and conditions that affect the brain and nerves.

Future Directions in Targeted Protein Degradation

The world of targeted protein degradation is changing fast. New ideas and discoveries are enhancing drug discovery. In the future, researchers want to improve the TPD technologies we have now. They plan to find new ways to make more proteins easy to target with drugs. They will also work on solving issues like drug resistance and how to deliver drugs effectively.

This ongoing search for new solutions will probably lead to better and more accurate treatments for TPD in different diseases. This progress can greatly improve human health.

knowledge about diseases and our genes, targeted protein degradation (TPD) could play a vital role in developing customized therapies that better help patients.

Conclusion

Recent advances in protein degradation are helping a lot in treating cancers like prostate and breast cancer. They focus especially on the estrogen receptor. New techniques using PROTAC molecules and molecular glue degraders show great potential. By understanding how these methods work at the molecular level, we can find new ways to target specific proteins for destruction. The use of bifunctional small molecules and zinc finger motifs has helped this field grow. This progress offers potential solutions for solid tumors and blood cancers. This new way looks very promising for the future of precision medicine and targeted therapies.