Many disease-driving proteins sit outside cells, where they have been difficult to remove with conventional medicines. A new study shows how they can be linked to the cell’s own waste-disposal system and sent for degradation. That opens a new way to treat diseases in which the problem is not only what a protein does, but that it keeps being there.
Disease-driving proteins rarely disappear on their own. In some cases, they can be slowed down or blocked – but they remain. In a new study, researchers from Denmark show that there may be another way: instead of simply targeting the proteins, we can use the body’s own waste disposal system to remove them.
“If we can bind a protein, we should also be able to make the body remove it. Instead of asking how to inhibit a protein, we asked: can we get the body to get rid of it?” explains Simon Glerup, Associate Professor at the Department of Biomedicine at Aarhus University.
A large share of the body’s disease-relevant proteins are located outside cells – in the blood, in tissues and on cell surfaces. They play a central role in diseases in which inflammation, scar tissue or accumulated proteins slowly damage the body but have been difficult to remove with existing technologies.
“Proteolysis-targeting chimeras – PROTACs – can do this inside the cell – the question was whether we could do something similar outside,” says Simon Glerup.
By linking disease proteins to a natural transport pathway into the cell, the researchers have now shown – in both cell experiments and animal models – that the body itself can draw them in and send them on for degradation.
“If binding itself is sufficient, it shifts the focus in drug development from function to presence,” he says.
A gap in medicine – and a route to the body’s waste system
For decades, drug development has been built around a single basic idea: finding a protein that drives disease – and then inhibiting it. This has been hugely successful, but it has also left a large unexplored area: disease proteins that are difficult to tackle with conventional drugs.
Proteins outside cells are particularly challenging. They make up a large share of the body’s proteins, but technologies such as PROTACs do not work on them because they rely on the cell’s internal degradation machinery.
“PROTACs work brilliantly for proteins inside the cell. But as soon as the target is not there, you cannot use that mechanism,” says Simon Glerup.
“When you are in the middle of it, it feels like an obvious next step. But seen from the outside, it breaks with a fundamental assumption about how we normally develop drugs. A large proportion of the interesting disease-related proteins are located outside the cell or on the cell surface. That is precisely where the classic degradation technologies cannot reach.”
When antibodies bind – but do not remove
This applies, for example, to signalling proteins, inflammatory factors and accumulated proteins in tissue – which play a central role in diseases such as arthritis, fibrosis and neurodegenerative disorders. Here, medicine has faced a dilemma: antibodies can bind to these proteins but do not necessarily remove them.
“If the binding is strong enough, it can be used to send the protein for degradation,” says Simon Glerup.
The inspiration came, in part, from earlier work on lysosome-targeting chimeras (LYTACs) and related technologies, in which large biological molecules can direct target proteins to lysosomes. But these approaches are complex and difficult to apply broadly.
“This showed that you could convert an antibody from binding its target into driving it towards degradation. Our question became whether you could do the same thing with small molecules – which, in principle, could be developed into something that can be taken as a pill,” says Simon Glerup.
From blocking proteins to sending them out as waste
The new approach changes the strategy. Instead of inhibiting a protein, it is labelled and directed towards degradation. The label is based on a small part of the natural interaction between the receptor sortilin and the protein progranulin – an interaction that normally causes cells to take up progranulin and send it to the lysosomes.
“The important thing is that we have identified a minimal motif capable of tagging something for degradation in the lysosomes. We are utilising a system that the cell already uses – but linking it to a new target,” says Simon Glerup.
The core of the technology is to combine two functions in one molecule: a “grabbing hook” that recognises the target protein and a “plug” that binds to sortilin on the cell surface. When the two are brought together, the cell perceives the complex as something that needs to be drawn in and sent on for degradation.
This triggers a process in which the complex is drawn into the cell and transported to the lysosome – the cell’s recycling and waste disposal centre – where the protein is broken down.
“Normally, an inhibitor has to bind to and occupy its target continuously. Here, in principle, the molecule simply needs to touch the target to set the process in motion. It is a shift from occupancy-driven to event-driven pharmacology – from holding something in place to triggering a process,” says Simon Glerup.
A molecular plug can turn existing drugs into degraders
The researchers also showed that this principle can be applied to existing drugs. Antibodies currently used to block disease proteins can be chemically modified so that they instead cause the protein to be broken down.
“If you already have something that binds to a disease protein, the binding itself no longer needs to produce the pharmacological effect. It is enough that it binds,” says Simon Glerup.
The technology, which the researchers call sortilin-based lysosome targeting chimeras (SORTACs), is designed as bifunctional molecules that bind both a target protein and sortilin – and has been demonstrated in the study on specific disease-relevant targets such as inflammatory cytokines and membrane proteins.
It differs from previous attempts to degrade extracellular proteins because it is both specific and flexible.
Previous strategies have often relied on broad mechanisms or struggled to target specific proteins precisely. Here, SORTACs function more like modular building blocks, in which, in principle, the part that recognises the target can be replaced.
Another step forward in the study is that degradation can be controlled not only by chemically attaching the tag. The small “degradation tag” can also be built directly into an antibody or a nanobody so that cells can, in principle, be programmed to produce targeted degraders themselves.
Why it matters
The study opens access to a group of proteins that have long been out of reach for medicine – particularly in diseases in which the problem is not just an overactive signal but the persistence of harmful proteins.
Many of them play a direct role in disease – not as passive markers but as active drivers of inflammation, tissue changes and intercellular signalling.
“What is interesting are the situations in which you have a clear disease target and a significant medical need – but in which existing technologies cannot solve the problem,” says Simon Glerup. “In such cases, degradation could offer a completely different approach.”
Today, many treatments require a drug to keep a disease-causing protein constantly in check. With degradation, the protein is removed.
“If we have something that can bind to a protein we want to get rid of, we can, in principle, link it to the same degradation module and have it removed,” says Simon Glerup.
Not all diseases – but the right protein targets
This could be significant in diseases in which the accumulation or persistent presence of proteins is part of the problem rather than simply their activity. Therefore, the most obvious targets are not all diseases but those in which a specific protein drives the disease – and in which patients still lack better treatments.
“That is one of the things we have spent the most time on: where is there a disease, a clear target and a significant unmet medical need that cannot be addressed with the existing toolbox?” says Simon Glerup.
The technology is still at an early stage. The current results have been achieved in controlled systems and in animal models, and significant development work still needs to be done before it can be tested as a treatment.
“We are focusing particularly on inflammatory diseases and neurological diseases at the moment,” says Simon Glerup.
How disease proteins are sent to the cell’s waste system
To demonstrate that the technology works in practice, the researchers designed a series of SORTACs – molecules capable of binding both a target protein and the sortilin receptor on the cell surface.
Sortilin was an obvious place to start because the receptor naturally transports proteins to lysosomes.
“Sortilin binds to progranulin, takes it into the cell and sends it to the lysosomes, where it is broken down. That was the natural mechanism we could hitch a ride on,” says Simon Glerup.
The researchers also knew from clinical trials in frontotemporal dementia that the human sortilin–progranulin system can be modulated. When sortilin is blocked, the level of progranulin rises significantly in both blood and cerebrospinal fluid.
“The clinical data told us that the mechanism is potent in humans – both in the periphery and in the central nervous system,” says Simon Glerup.
Therefore, the researchers did not use a random transport system but a mechanism that had already proven to be stable and modifiable over time.
From cells to animals: the whole chain had to work
In the initial experiments, the researchers demonstrate that their SORTAC molecules can bind simultaneously to both sortilin and the selected target proteins. Once that link is established, the crucial step occurs: the protein is taken up into the cell and transported to the lysosomes, where it is broken down.
“It only works when the molecule binds to both the target and sortilin. It is this binding that causes the cell to take the target inside,” says Simon Glerup.
The effect is selective: the SORTAC molecule does not act as a general vacuum cleaner. It only removes proteins it has linked to sortilin, because degradation requires a specific complex between the target and the receptor.
“The important thing is that we are not simply activating a general clean-up system. We link the degradation to the target we specifically want to get rid of,” says Simon Glerup.
In addition, the study shows that the technology is not limited to large biological molecules such as antibodies. It can also be applied to smaller, chemically synthesised molecules, which are easier to design, adjust and, in some cases, develop into tablet-based treatments.
The next step was to test whether the system also works outside cell experiments. In animal models, the researchers show that target proteins are reduced in both blood and tissue following treatment – a crucial step, since it demonstrates that the entire mechanism also functions in a living organism.
“The important thing was to show that it does not just work in an artificial system in a Petri dish, but also when the whole biological system is involved,” says Simon Glerup.
Nor is the effect limited to the moment the molecule binds; it follows the same principle as PROTACs: a single binding can trigger a repeatable degradation process. In the small-molecule format, the SORTAC molecule itself is not degraded in the lysosome. It can release its target, come back out and start a new round – like a tiny reusable transporter.
“That is why a single copy of the molecule can take out many copies of the target,” says Simon Glerup.
Like LEGO: a system that can be rebuilt for new targets
A crucial element of the study is that the technology is not limited to one specific protein.
The researchers demonstrated that the part of the SORTAC molecule that recognises the target can be replaced, thereby directing the technology towards different proteins.
“It is a bit like building with LEGO. You have one module that recognises the protein you want to get rid of and another module that connects it to the cell’s waste-disposal system,” says Simon Glerup.
In the study, the researchers demonstrate this, among other things, on immune proteins and signalling molecules that play a central role in inflammation.
The study shows, first and foremost, that proteins outside the cell can be bound, linked to sortilin, drawn into the cell and broken down – and thus not merely affected but actually removed.
“It is not just about blocking the target. It is about driving it all the way to degradation,” says Simon Glerup.
The crucial thing is that the process is controlled.
“Specificity is absolutely central. Otherwise, this would not be useful,” he says.
But the results also have clear limitations. Although the technology works across cell experiments and animal models, the study does not yet show whether it can be translated into a treatment safe for humans, how long the effect lasts or how repeated activation of the sortilin system will affect different tissues.
“It is still early days. The next step is to show how well it holds up when developed for specific diseases,” says Simon Glerup.
How broadly the technology can be used remains unclear.
When the problem is that the protein stays
The study does more than show that a protein can be removed. It extends the reach of medicine to disease-causing proteins that have so far been difficult to treat.
“For many years, we have had good tools inside the cell but not outside it,” says Simon Glerup.
In this new work, the researchers are linking two systems that have previously been separate in drug development: disease proteins outside the cell and the cell’s own degradation machinery inside the cell.
This is particularly important for diseases in which simply blocking a protein is not enough. In chronic inflammation, signalling proteins can continue to drive tissue damage. In neurodegenerative diseases, proteins can accumulate between cells. Here, the problem is not just what the protein does – but that it continues to be present.
“Protein aggregates are interesting because it is possible to create something that binds them. But the question is what happens next. The idea here is not just to bind the aggregate but to drive it towards degradation,” says Simon Glerup.
A new link between disease proteins and the cell’s clean-up system
The study does not yet show how widely this approach can be applied or how precisely the process can be controlled in different tissues.
But it establishes a link that was previously missing: a controlled pathway from proteins outside the cell to the cell’s own degradation system.
In practice, this broadens the range of proteins that can be considered possible drug targets. Not because all proteins thereby become easy to treat but because binding in itself may be enough to trigger a therapeutic effect – particularly for diseases in which the very presence of the protein is the problem.
“There are proteins you can effectively bind to a single site with an antibody or a small molecule,” says Simon Glerup. “But if the problem is that the entire protein continues to be present, it may be more rational to remove it.”
