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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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« The Baran Group Blog (And Some Others?) | Main | Sirtis Gets Shut Down in Cambridge »

March 12, 2013

Resveratrol Gets Some Details Cleared Up

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Posted by Derek

I've been meaning to write on this paper, from David Sinclair and co-workers, on the mechanism of resveratrol action. The backstory is so long and convoluted that you're going to have to set aside some time to catch up if you're just joining it (paging back through this category archive will give you some play-by-play). But the basics are that resveratrol came on the scene as an activator of the enzyme SIRT1, which connection was later called into question by work that showed a lot of artifacts in the assay conditions used to establish it.

This new paper may well clear some of that up. The fluorescent tagged peptides that were producing the false positive may well be mimicking the natural protein partners, if this analysis is correct. SIRT1, as it turns out, recognizes a hydrophobic domain in the same region of each, which can be the fluorescent tag, or native hydrophobic amino acids themselves.

So it appears that resveratrol (and other synthetic sirtuin activators) are acting allosterically on the protein. This work found a single SIRT1 amino acid mutant (E230K) that doesn't affect SIRT1's catalytic activity, but does completely mess with resveratrol's ability to activate it (the other compounds in this class show the same effect). That makes for a neat story, and it would resolve several questions about the molecular mechanism of action.

But it leaves open the bigger questions: is SIRT1 a human drug target? Do activators exert beneficial effects, and do different ones have different profiles in living systems? There's already plenty of evidence for some of these; the problem is, the evidence points both ways (much of this is summed up and linked to in this post). Resveratrol itself is not, I would say, an appropriate molecule to answer the detailed questions (other than "What does effects does resveratrol itself have?"). It does not have particularly good pharmacokinetic properties, for one thing, and it is known to hit a lot of other things besides SIRT1 (Sinclair himself has referred to it as a "dirty molecule", and I agree).

So it's the follow-on sitruin activators that GSK has that are the real vehicles for answering these very interesting (and potentially important, and potentially lucrative) questions. A quick look at Clinicaltrials.gov shows that work has been done on SRT2104 and SRT2379, but many of these studies have been complete for a year or two now. (Here's the one that's listed as ongoing - it and several others have an anti-inflammatory bent). All we can deduce is that at least two SRT compounds are being (or recently have been) evaluated in the clinic. Fierce Biotech has a bit more from Sirtris CEO George Vlasuk:

About those clinical trials: GSK's massive investment in Sirtris has yet to lead to a drug or a prime-time drug candidate. Sirtris has ended clinical development of multiple synthetic compounds after initial human studies, Vlasuk said. And his team is hunting for the precise mechanism for activating SIRT1 in hopes of creating more potent compounds than resveratrol to treat diseases.

Hmm. I thought that maybe this new Science paper was the precise mechanism. But maybe not? The story continues. . .

Comments (9) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. nitrosonium on March 12, 2013 12:20 PM writes...

thanks so much for covering this. i have been watching/listening to news coverage of this latest report (especially in light of the Sirtirs/GSK history covered here). it is amazing to see how science findings get distilled down for public consumption.

simply consume an entire vineyard in one sitting and you'll live to be 1000!!!!

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2. annonie on March 12, 2013 12:29 PM writes...

This does not acknowledge the side effects due to interactions with other targets of biological effect.

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3. barry on March 12, 2013 12:43 PM writes...

ast the core of Drug Discovery is Research, at the core of Research is Science and at the core of Science is Falsification. There is nothing more important to Drug Discovery than falsifying the premise that (in this case) Sirt1 is a valid drug target. That may not be an easy thing to do (and if it can't be done, then the expense and effort of a drug discovery effort is justified). But too often egos keep a project alive and on budget for years rather than do the key experiment that risks disproving the putative target's relevance to human disease.

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4. oldnuke on March 12, 2013 2:58 PM writes...

@1: Or you just FEEL like you're 1000 years old!

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5. David Borhani on March 12, 2013 4:48 PM writes...

Not having waded through the details (including an 80 page SI), though I do intend to, does anyone understand how potential off-target effects of the STAC compounds were ruled out?

They are weak (uM) SIRT1 modulators, and yet they look poised for off-target (especially kinase) binding.

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6. Doyle on March 12, 2013 7:06 PM writes...

Maybe super activation of SIRT1 is not healthy. Maybe moderate doses of resveratrol (250 to 500 mg/day) hit the 'sweet spot'....i.e. on easy to swallow, non patentable pill per day...Big pharma nightmare.

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7. Webster on March 13, 2013 10:36 AM writes...

#6 - Indeed, or pigs could fly...big nightmare for the aviation industry.

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8. Doyle on March 13, 2013 10:51 PM writes...

#7 - FDA APPROVED! - this drug may cause thoughts of suicide, certain cancers, dry mouth, redness or rash, irregular heartbeat, serious profits, diarreha, the ability to Abilify!

Cant we all just get along!

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9. Tuck on April 4, 2013 1:40 PM writes...

See this?

"...Then, last Tuesday, GlaxoSmithKline suddenly announced that it was shutting down its Sirtris division, the Boston-based company that was actually supposed to be making the “red wine pills,” and which GSK had bought for $720 million just five years ago. Wait, what?..."

“Dude, Where's My Red Wine Pill? The strange saga of resveratrol, the wonder drug that never was.”
http://www.newrepublic.com/article/112706#

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