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September 28, 2009
Chew On This, Enzyme
File this one under "Department of Odd Ideas". There's a paper coming out in JACS that has a neat variation on an idea that's been kicking around for some years now: molecularly-imprinted polymers (MIPs). A MIP is a sort of molded form around some molecular template - you make your polymer in the presence of the desired target molecule, with the idea that you'll then form target-shaped cavities in the resulting gel.
These things have been worked on for years in the analytical chemistry field, since they have the potential to form very robust sensors for a wide variety of substances. The thought has also been that they might serve as pseudo-enzymatic catalysts for some reactions as well, although I get the impressions that that's been harder to realize. From the outside, the whole area seems to be one of those that goes on for years as something that's still developing and hasn't quite taken off.
This latest idea may or may not change that, but it's ingenious. What this group (from two French labs) has done is anchor the initiation point of the polymer to an enzyme inhibitor molecule - in this case, to an amidine inhibitor of trypsin. The resulting polymer turns out to have strong inhibitory activity for the enzyme, about a thousandfold higher than the starting amidine - as well it might, if it's muffling the active site like a huge beach towel. They tried a number of potential polymeric systems, settling on some neutral methacrylates, since charged species didn't seem to give binding (or specificity) at all.
The control experiments support their interpretation of what's going on. The resulting polymers don't seem to recognize (or inhibit) a variety of otherwise similar proteins. If control polymers are formed without the anchoring group, they have no inhibitory effect. Similarly, if the experiment is done with an excess of non-polymerizable inhibitor, the effect goes away as well (since the active site is already occupied).
I'm not sure that these things will find much use as enzyme inhibitors in living systems, unless you're looking to shut down some sort of enzyme in the gut. (In that case, you might be able to give someone a glass full of soluble polymeric stuff, with the expectation that it wouldn't be absorbed and would emerge more or less unchanged. But perhaps there are applications under blood filtration or dialysis conditions, or topical ones. At any rate, it's a neat idea which is now looking for a home. . .
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