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


In 2016 Aubrey de Grey highlighted the newly created PrECISE method that will allow protease engineering:

Intracellular FRET-based Screen for Redesigning the Specificity of Secreted Proteases.

The list of human proteins capable of forming toxic amyloids seemingly grows every year, from well-known examples such as β- amyloid, alpha-synuclein and the prion protein to more obscure cases - transthyretin, atrial natriuretic factor, β2 microglobulin, and so forth. This most likely reflects a general spectrum of amyloidogenicity, with certain peptides relatively aggregation-prone but many others capable of following the same path given sufficient time and/or particular external factors (such as failures of proteostasis^20^). Thus, we should expect the prevalence and medical significance of the amyloidoses to increase in line with population aging. Although the de novo design of proteins able to catalyse arbitrary reactions has in the last few years begun to move from wishful thinking to reality, the published examples of such work still rely heavily on directed evolution after the design stage to achieve useful efficiencies; also, rational techniques inevitably require large investments of time and very specific expertise. In order for protein re-engineering to become a mainstream tool, methods suited to less specialised research groups - like the PrECISE technique introduced in this thesis - will be required. Thankfully, ever-accelerating advances in computational power and experimental automation continue to both increase the power and reduce the costs of such methods; the author notes that the
sheer scale of the screen performed was critical to her success. Meanwhile the trend towards outsourcing of repetitive experimental procedures to contract research organisations gives some credibility to the notion of "directed evolution as a service". It will remain critical to consider whether a model peptide is in fact a clinically valid target given that the exact fold adopted, and not merely the primary sequence, is generally of concern^21^. However, comparing the experimentally determined structures of both should generally suffice to resolve this, and techniques for determining structures without the notoriously difficult step of crystallisation are also advancing swiftly. Of course, the applications of directed enzymatic evolution are not limited to protein targets. A similar method could be used in any case where the pathological agent can be formulated as a bridge between the FRET pair, so long as a parent enzyme exists with at least some limited capacity to drive the desired reaction."

Posted by: jimofoz at March 28th, 2019 5:47 AM
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