September 30, 2020

Degrading Drugs for Problem Proteins: Journal Club Now On Bio Eats World (ep 2) | a16z

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

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).

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

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 = 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

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

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

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