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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
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Notes By Maryann

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