All the proteins inside our cells are destroyed and rebuilt quite regularly, as a way to keep them in a generally undamaged state. Some of the proteins outside our cells, however, are laid down early in our life and then never recycled at all, and some others are only recycled very very slowly. These long-lived proteins are susceptible to chemical reactions. Luckily, the function of long-lived proteins tends to be very simple -- they don't catalyse chemical reactions, for example, the way that enzymes do. In general they have a biophysical function -- they give a tissue elasticity (as in the artery wall) or transparency (as in the lens of the eye) or high tensile strength (as in ligaments). Occasional chemical reactions with other molecules in the extracellular space don't affect these functions very much -- at first. But in the long run, they can matter a lot, especially in the case of the artery wall, which becomes much more rigid and leads to high blood pressure. The type of chemical reaction that causes this loss of elasticity is one that results in a chemical bond (a cross-link) between two nearby proteins that were previously able to slide across or along each other.

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. And 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. These chemists formed a company (named Alteon) to market the drug (named ALT-711), but it is still in clinical trials.

We need more work in this area. There are plenty of other types of cross-link that ALT-711 doesn't break, so we need other chemicals that will complement what ALT-711 does. Some such crosslinks are probably too stable to be breakable catalytically by any non-toxic small molecule; here it may be necessary to find enzymes that can couple the link-breakage to hydrolysis of ATP (which might need the enzyme to shuttle back and forth across the cell membrane, as there is very little ATP in the extracellular space) or else to use the concept of "one-shot" proteins, such as the DNA repair protein MGMT, which react with a stable molecule but thereby inactivate themselves. This is a feasible approach because of the very low rate of formation of the relevant cross-links: the cellular energy budget would not be significantly impacted.

Talks on this topic at IABG 10:
Lakatta