GlycoSENS
Breaking extracellular cross-links.
All the proteins inside our cells are destroyed and rebuilt quite regularly, as a way to keep them in a generally undamaged state. Sometimes these mechanisms are incomplete – a problem which I address in the section on junk inside cells – but they are generally satisfactory.
Some of the proteins outside our cells, however, are laid down early in our life and then never recycled at all; while some others are only recycled very slowly. The proper functioning of the tissues composed of these structural proteins – the elasticity of the artery wall, or the transparency of the lens of the eye, or the high tensile strength of the ligaments – relies on their maintaining their proper structure. But chemical reactions with other molecules in the extracellular space occasionally result in a chemical bond (a so-called crosslink) between two nearby proteins that were previously free-moving, impairing their ability to slide across or along each other. This effect is especially prominent in the case of the artery wall, which becomes much more rigid as its proteins are crosslinked – leading to high blood pressure.
The Solution
Luckily, it happens that a lot of the cross-links that accumulate in this way have very unusual chemical structures, not found in proteins or other molecules that the body makes on purpose. This means that it is theoretically possible to identify chemicals that can react with the cross-links and break them, without reacting with anything that we don't want to break. Indeed, several years ago a group of chemists found such a molecule, which has now been tested in many different animals and also in humans and seems to lower blood pressure quite substantially – especially the kind of blood pressure ("systolic") most directly elevated by crosslinking in the vessel walls. These chemists formed a company (named Alteon) to turn their discovery into an FDA-approved drug for systolic hypertension and several other diseases related to the crosslinking of proteins. The drug (named ALT-711, or alagebrium), has been moderately successful in preliminary clinical trials, but its progress through the drug development pipeline has been slowed considerably by financial difficulties with the company.
However, there are plenty of other types of crosslink that alagebrium doesn't break, so we need other chemicals that will complement what alagebrium does. Many such crosslinks will be breakable with simple, small-molecule drugs like alagebrium itself, but it's likely that at least some of them will turn out to be too stable for this approach. It will therefore be necessary to investigate more sophisticated approaches, such as:
- Finding or engineering enzymes to break the crosslinks. Enzymes are potentially more effective than drugs in this application because they can use cellular energy (ATP) to fuel the reaction. Such an enzyme might need to shuttle back and forth across the cell membrane, as there is very little ATP in the extracellular space. Fortunately, the very low rate of formation of the relevant cross-links makes it likely that this requirement would not significantly impact the cellular energy budget.
- Developing "one-shot" proteins, on the model of the DNA repair protein MGMT, which would break the crosslink but would themselves be destroyed in the process. Again, this is a feasible approach because the relevant cross-links form so slowly that we will only have to use a relatively small number of such molecules to clear most of them out of our tissues.
Our Work
Resources
Talks on this topic at IABG 10: Lakatta
At SENS3: Moreau