PROTACs and LYTACs: How therapeutics can take advantage of proteomic garbage men
Cells are biological marvels, but even they need help taking out the trash sometimes.
Cells are biological marvels, but even they need help taking out the trash sometimes.
This is especially true when things go awry!
Cells have mechanisms in place to degrade misbehaving proteins, eliminate things that aren’t needed anymore, or respond to crises by going nuclear.
For cells, the nuclear options are autophagocytosis (self-eating), senescence (cell cycle arrest), apoptosis (programmed cell death), and necrosis (rapid, less programmed, cell death).
But, in some diseases these processes are interrupted and unruly proteins are allowed to continue their delinquent behaviors.
Things can get even worse when cells that should have pushed the red button and sacrificed themselves for the good of everyone else, don’t.
So, how can we use proteomics to get these cells back on track (or obliterate them)?
Well, cells have two distinct protein waste removal services that we can take advantage of:
The Proteasome - These are like protein wood chippers that float around inside a cell. They’re used to chop up useless, misfolded, damaged, or no longer needed proteins!
The Lysosome - Is a specialized membrane enclosed organelle (kind of like an industrial garbage dump) where bulk protein degradation activities take place.
Targeted protein degradation using these two pathways has been an important area of therapeutic development in the last few years.
This work has focused on the creation of ‘chimeric’ molecules that combine the function of two or more molecules together to perform a desired function:
PROteolysis TArgeting Chimeras (PROTACs) - The proteasome degradation pathway is activated when the proteasome comes across proteins that have been tagged with a molecule called ‘ubiquitin.’ This tag is added to proteins by an enzyme, E3 ubiquitin ligase. So, most PROTACs are composed of two components, one that binds the protein we’d like to degrade, and another that binds E3! This brings that protein into very close proximity to the enzyme that marks things for destruction - bada bing, bada boom - no more protein!
LYsosomal TArgeting Chimeras (LYTACs) - The lysosome degrades lots of things including food that’s been brought in from outside the cell (phagosomes), receptors that once resided on the cellular membrane (endosomes), and larger cellular structures like mitochondria (autophagosomes). How all of those things get to the lysosome is pretty well known, and chimeric molecules can be engineered to cause target proteins to be scooped up in one of those ‘-somes’ and degraded in the lysosome! Just like PROTACs, these chimeric combinations involve binding to a target of interest on one end, and to a lysosomal targeting protein/molecule on the other!
PROTACs and LYTACs have shown promise as adept therapeutic garbage men in inflammatory disease (degrade misbehaving receptors), neurodegeneration (target plaque forming proteins), and cancer (initiate cell death).
See, taking out the trash isn't so boring after all.
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Brian Krueger