
September 30, 2020
Degrading Drugs for Problem Proteins: Journal Club Now On Bio Eats World (ep 2) | a16z
Key Takeaways
- Conventional drug mechanism can’t get 100% of protein blocked
- Degraders have more axes of effect
- Proteolysis targeting chimera (PROTAC) degraders function on proteins inside the cell but newer LYTAC degraders can target proteins in extracellular space
- Extracellular proteins should now be added to the list of potential targets for degradation strategy
- Lysosome-targeting chimera drugs (LYTAC) may have future therapeutic in amyloid diseases such as Alzheimer’s and Parkinson’s disease
Introduction
Lauren Richardson (@lr_bio) hosts researcher @carolynbertozzi, to discuss her newly developed class of drugs and associated mechanism.
Article: Lysosome-Targeting Chimaeras For Degradation Of Extracellular Proteins by Steven Banik, Kayvon Pedram, Simon Wisnovsky, Green Ahn, Nicholas Riley, and Carolyn Bertozzi, published in Nature (2020).
Mechanism of Conventional Drugs
- Bind to target, usually a pathogenic target or protein in the body contributing to disease
- Occupancy driven pharmacology = drug binds to target and blocks function
- For example, ibuprofen binds to an enzyme and blocks its activity which in turn blocks the inflammatory pathway
- Limitation: can’t get 100% of protein blocked
Benefits of Degrader Vs. Conventional Drugs
- Degrader can bind to target and eliminate so you reduce the level of a target protein
- Most proteins have multiple dimensions to function
- When you block the protein, there are probably other interactions of protein not affected
- When you degrade protein entirely, you take away all functions of protein
- Degrader has more axes of effect
PROTAC: New Class of Drugs
- PROTAC = proteolysis targeting chimera
- A new way to shutdown pathogenic protein is to target for degradation
- In nature, the central mechanism for the degradation of proteins in a cell is to mark for ubiquitin chains which signals degradation
- Concept: build a molecule that builds a gap between targeted protein and ubiquitin machinery
- Mechanism: PROTAC can bind to target proteins and bring enzyme to it which adds ubiquitin
- PROTAC puts ubiquitin on and drives degradation
- Using endogenous mechanism to target a wider range of proteins that would be possible with an inhibitor
Limitations of PROTAC
- Not all proteins are accessible by PROTAC
- PROTAC processes function on protein inside the cell (cytosol or nucleus)
- But there’s a whole world of proteins outside the cell (i.e., on cell surface) or secreted by cell and released in extracellular space
LYTAC: Lysosome Targeting Chimera Cellular Pathway & Mechanism
- LYTAC was born out of the need to identify other mechanisms of reaching proteins not found inside a cell
- Degradation strategy provides a more potent effect with lower doses
- Nature uses the endosome-lysosome pathway: cells will internalize and engulf molecules from extracellular space into endosomal vesicles
- LYTAC mimics the natural degradation pathway of the endosome-lysosome pathway
- Mechanism: one part binds protein you want to degrade, other part binds the lysosomal-trafficking receptor system
- Molecules interact with receptors and bind to a target of interest
- Specificity and affinity are keys
Next Steps
- Extracellular proteins should now be added to the list of potential targets for degradation strategy
- Group is currently undergoing second and third-generation improvements of LYTAC technology
- Improve structure: new chemistry to be more engineered to identify the best geometry for target
- Develop LYTACs from other molecules
- Improvements to the ability to target different receptors via lysosomal trafficking
Future Use of LYTAC Drugs
- Therapeutic applications hopeful for diseases that involve the aggregation of proteins in an extracellular environment
- LYTAC approach can potentially treat amyloid diseases such as Alzheimer’s and Parkinson’s