Hijacking the Proteasome to Dispose of Unwanted Molecules in Age-Related Disease

Cells are equipped with a protein disposal system in the form of the proteasome. Damaged or excess proteins are tagged with ubiquitin, and shuttled to the proteasome where they are dismantled into component parts that can be reused to build new proteins. The popular science article noted here discusses an approach to interfacing with this cellular maintenance system that is presently under developement, delivering carefully designed molecules that ensure a specific protein is tagged with ubiquitin, thus persuading the cell to destroy it. Over the course of aging, cells become exposed to any number of unwanted forms of molecular waste, many of which are proteins of one sort or another, and it is possible that finding ways to deliver those molecules to the proteasome could prove to be an effective therapy.

The drug strategy, called targeted protein degradation, capitalizes on the cell's natural system for clearing unwanted or damaged proteins. These protein degraders take many forms, but the type that is heading for clinical trials this year is one that researchers have spent more than 20 years developing: proteolysis-targeting chimaeras, or PROTACs. Because they destroy rather than inhibit proteins, and can bind to them where other drugs can't, protein degraders could conceivably be used to go after targets that drug developers have long considered 'undruggable': cancer-fuelling villains such as the protein MYC, or the tau protein that tangles up in Alzheimer's disease.

In diagrams, PROTACs often look like dumb-bells. They are molecules made up of two binding ends connected by a thin tether. The action happens on the ends. One grabs on to the target protein, while the other latches on to a ubiquitin ligase - part of the cell's natural rubbish-disposal system that labels defective or damaged proteins by slapping a small protein called ubiquitin onto them. Ubiquitin tags act as sort of 'Please collect' stickers that instruct the cell's protein shredder, called the proteasome, to do its thing.

Proximity accounts for a lot in biology, so by simply bringing together the ligase and the target protein, a PROTAC ensures that the target will get marked for destruction. Ligases are efficient and ubiquitin, as the name suggests, is plentiful, so a single PROTAC should be able to perform its catch-and-release function repeatedly throughout the cell, suggesting that only a small amount of such a drug is needed for potent activity.

Link: https://www.nature.com/articles/d41586-019-00879-3