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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

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September 6, 2007

More Things Than Are Dreamt Of

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Posted by Derek

It’s useful to be reminded every so often of how much you don’t know. There’s a new paper in PNAS that’ll do that for a number of its readers. The authors report a new protein, one of the iron-sulfur binding ones. There are quite a few of these known already, so this wouldn’t be big news by itself. But this one is the first of its kind to be found in the outer mitochondrial membrane, which makes it a bit more interesting.

It also has a very odd structure – well, odd to us humans anyway, for all we know things like this are all over the place and we haven’t stumbled across one until now. There’s a protein fold here which not only has never been seen in the 650 or iron-sulfur proteins with solved structures, it’s never been seen in any protein at all. That’s worth a good publication, for sure.

The part that’ll really throw people, though, is that this protein (named mitoNEET, for the amino acids that make up its weird fold) binds a known drug whose target we all thought we already knew. Actos (pioglitazone) turns out to associate with it, which is a very interesting surprise. We already knew the glitazones as PPAR-gamma ligands. We didn’t understand them as PPAR ligands (no one understands them very well, despite many years and many, many scores of millions of dollars), but that was generally accepted as their site of action.

And now there’s another one, which is going to make the pioglitazone story even more complex. Reading between the lines of the paper, I get the strong impression that the authors were fishing for another pioglitazone binding site, using modified versions of the drug to label proteins, and hit the jackpot with this one. (And good for them - that's a hard technique to get to work). There’s been some speculation that the compound might have effects on mitochondria that wouldn’t necessarily be PPAR-mediated, and this is strong circumstantial evidence for it.

What’s more, I can’t think of any other iron-sulfur proteins that are targets of small molecules. Just last week, I was talking about the diversity of binding sites and interactions that we haven’t explored in medicinal chemistry, and here’s an example for you.

This paper raises a pile of questions: what does mitoNEET do? Shuttle iron-sulfur complexes around? (If so, to where, and to what purpose?) Is it involved in diabetes, or other diseases of metabolism? Does pioglitazone modify its activity in vivo, whatever that activity is? How well does it bind the drug, anyway, and what does the structure of that complex look like? Does Avandia (rosiglitazone) bind, too, and if not, why not? Are there other proteins in this family, and do they also have drug interactions that we don’t know about? Ah, we’ll all be employed forever in this business, for as long as people can stand it.

Comments (3) + TrackBacks (0) | Category: Biological News | Diabetes and Obesity


COMMENTS

1. SynChem on September 6, 2007 9:55 AM writes...

I wonder if they have binding assay data for Actos. Without that piece of the puzzle, this means nothing. Actos could well be a very weak high uM binder, in which the case I say so what.

It's interesting nonetheless. I bet if one does this kind of exercise to other drugs with "known" targets, he'd get these drugs to co-crysalize with a million other proteins of various classes. And again, this alone doesn't necessarily mean anything regarding the drugs' mechanism of action.

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2. Boghog on September 6, 2007 10:44 AM writes...

@SynChem:
I wonder if they have binding assay data for Actos?

Reference #6 of the PNAS paper cited above (Colca, JR, et al., 2003)reports that "half-maximal binding [for pioglitazone] occurs between 0.1 and 1.0 uM" which is in the same range as the affinity of pioglitazone for PPAR-gamma.

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3. SynChem on September 6, 2007 1:29 PM writes...

Boghog,

Well, the story just got a lot more interesting...

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