Lauren Richardson (@lr_bio) hosts researcher @carolynbertozzi, to discuss her newly developed class of drugs and associated mechanism.

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

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