Mickey Kaus, in his link to yesterday's post, mentioned that the company I work for seems down on peptides as drugs, and asked his readers to keep that in mind when they read my opinion on endostatin. All I can say is, it isn't just me (or my company.) You won't find much of anyone trying to develop a small protein as a drug. They're just too tempting for a variety of enzymes to tear up; this is a problem that's been known for decades.

Larger proteins, oddly, can have a bit more potential, although not for oral dosing. Depending on how they're folded, they can have a decent half-life in circulation, if you can get them that far (or, failing that, the effects they set off can be reasonably long-lasting.) Insulin and interferon are two examples that come to mind, both of which have to be injected, but work well.

There's been a huge amount of work devoted to making proteins stable enough to be given orally. Usually, the sorts of changes you have to make are also big enough to wipe out the activity you wanted, too. But there are some techniques that can work - attaching a long polyethylene glycol chain is a good one, known to the cognoscenti as "PEGylation." Glaxo SmithKline just signed a deal with a small company that is doing just this sort of thing to insulin. Many schemes have been hatched for encapsulating the proteins in some sort of vehicle that'll sneak them past the gut enzymes, with decidedly mixed success.

And there are ways to get around the digestion problem completely. It turns out that large proteins cross the nasal mucosa into the bloodstream surprisingly well (no, in case you're wondering, cocaine isn't in this category - it's a small molecule.) Several companies are working on this, with an inhaled form of insulin in advanced clinical trials (it's had its problems.)

For small proteins, there are all sorts of ways to modify the peptide bonds to make them less attractive to enzymes (putting in the wrong-handed amino acid, unusual methyl groups, other bonds instead of the usual amino acid amide connection, and so on.) It's a hard living, because many of these changes also get rid of the original protein's activity, and they don't always increase the levels in circulation, either. If you're going to go the peptidomimetic route (many have,) then you need some commitment, because it could take a while.