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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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« Are You Now, Or Have You Ever Been. . .? | Main | Thoughts on What Used to Be Schering-Plough »

November 5, 2009

What Exactly Does Resveratrol Do?

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Posted by Derek

Resveratrol's a mighty interesting compound. It seems to extend lifespan in yeast and various lower organisms, and has a wide range of effects in mice. Famously, GlaxoSmithKline has expensively bought out Sirtris, a company whose entire research program started with resveratrol and similar compound that modulate the SIRT1 pathway.

But does it really do that? The picture just got even more complicated. A group at Amgen has published a paper saying that when you look closely, resveratrol doesn't directly affect SIRT1 at all. Interestingly, this conclusion has been reached before (by a group at the University of Washington), and both teams conclude that the problem is the fluorescent peptide substrate commonly used in sirtuin assays. With the fluorescent group attached, everything looks fine - but when you go to the extra trouble of reading things out without the fluorescent tag, you find that resveratrol doesn't seem to make SIRT1 do anything to what are supposed to be its natural substrates.

"The claim of resvertraol being a SIRT1 activator is likely to be an experimental artifact of the SIRT1 assay that employs the Fluor de Lys-SIRT1 peptide as a substrate. However, the beneficial metabolic effects of resveratrol have been clearly demonstrated in diabetic animal models. Our data do not support the notion that these metabolic effects are mediated by direct SIRT1 activation. Rather, they could be mediated by other mechanisms. . ."

They suggest activation of AMPK (an important regulatory kinase that's tied in with SIRT1) as one such mechanism, but admit that they have no idea how resveratrol might activate it. Does that process still require SIRT1 at all? Who knows? One thing I think I do know is that this has something to do with this Amgen paper from 2008 on new high-throughput assays for sirtuin enzymes.

One wonders what assay formats Sirtris has been using to evaluate their new compounds, and one also wonders what they make of all this now at GSK. Does one not? We can be sure, though, that there are plenty of important things that we don't know yet about sirtuins and the compounds that affect them. It's going to be quite a ride as we find them out, too.

Comments (35) + TrackBacks (0) | Category: Aging and Lifespan | Biological News | Drug Assays


COMMENTS

1. JAB on November 5, 2009 9:13 AM writes...

Just yesterday I heard a seminar by John Pezzuto, the initial "discoverer" of resveratrol's effects. His take on mechanism is that it's doing a lot of things, and which ones are important to the in vivo effects are not at all clear, even yet, after many years of investigation by a lot of folks. This all highlights the importance of using several orthogonal assays at the molecular level to weed out artifacts. And even then, there are dirty molecules which won't sort out into clear mechanistic categories. Dirty molecules are probably a lot more common than the "clean" ones.

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2. floyd on November 5, 2009 9:40 AM writes...

If you go back and reread the comments from your original April 08 post, you'll see that comment #6 was pretty much right on target. JAB is correct. Resveratrol is in a large class of similar "dirty molecules" with miracle properties that can't be explained or optimized. That's because these molecules stick to a wide range of proteins with a wide range of affinities. I'm not saying they're bad. I have a glass of wine every night and had an apple every day on the way home from work, back when I had a job.

Glaxo, which has little or no natural product expertise and is fast losing its experienced (ie expensive) scientists, was taken to the cleaners on resveratrol. So was 60 minutes.

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3. Bill Sardi on November 5, 2009 10:15 AM writes...

We conducted a study to compare global gene expression emanated from calorie restriction (CR), trans resveratrol and a matrix of molecule similar to those found in red wine (resveratrol, quercetin, IP6 phytate). CR significantly differentiated 198 genes, resveratrol 225 genes, the resveratrol-based matrix 1711 genes. The matrix exerted this effect at a resveratrol dose 17-320 times lower than prior studies. This may be the key secret of red wine -- it provides an array of molecules that work synergistically at low dose. The optimal health range for wine is 3-5 five-ounce glasses, which provide ~180-300 mg of grape polyphenols. This could be concluded to be the safe and effective range. Indeed, the work of Dipak Das at University of Connecticut shows resveratrol in the dosage range of 175-350 mg limits damage to the heart from a heart attack but higher doses (1750-3500 mg) are deleterious. Just exactly what the prospect of super-Sirtuin activators are now is unknown. Resveratrol is a miracle molecule, but its genetic mechanisms are in question. Its advantage is its broad genomic action, not its ability to stimulate one gene. In fact, disease and aging involves many genes, not one. -Bill Sardi, Resveratrol Partners LLC, dba LONGEVINEX

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4. Vader on November 5, 2009 10:36 AM writes...

Glad to hear work is being done on the virtues of sirtuins.

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5. Sili on November 5, 2009 12:00 PM writes...

Fluor de Lys

I love puns.

Yet another reason I shouldn't publish.

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6. Anonymous on November 5, 2009 12:38 PM writes...

The claim that resveratrol activates Sirt1 was always ridiculous. Just look at the structure of the molecule and the concentrations they used. The question is how this myth was perpetuated for so many years, even after it was refuted in published papers. and also how even excellent blogs like this one fell for it, repeatedly...

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7. Hap on November 5, 2009 12:46 PM writes...

No, but you can edit for Angewandte.

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8. alig on November 5, 2009 1:34 PM writes...

GSK paid a dear price for this folly. Several hundred scientists lost their jobs to pay for a company based on flawed science. Moncef and Patrick ignored their internal scientists and bought the company anyway. One of them should man-up and quit over their mistake, but we all know that won't happen.

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9. Hap on November 5, 2009 1:47 PM writes...

Resveratrol activates the (well-known) Slaver-over-small-pharma-antiaging-drugs/Buy-small-pharma-and-outsource-your-discovery-chemists (Sospad/Bspodc) pathways, which apparently inhibit the development of healthy balance sheets in pharma while also inhibiting the dreaded executive apoptosis genes. The mechanisms of action, however, have not been well explored and are unknown at this time.

The activity may be analogous to the activation of the Make-big-molecules pathway in academic synthetic organic chemists (and funding agencies) by taxolXXXXXpaclitaxel.

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10. anchor on November 5, 2009 4:21 PM writes...

GSK does not care, it's all business decision (eliminate some 500-1000 people and recover the cost). If it teaches anything, it is that "haste makes waste" in a World of "greed is good".

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11. MTK on November 5, 2009 4:39 PM writes...

a $700 million purchase partially based on a faulty assay? I think they care. They probably won't admit it, but oh yeah. They care.

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12. metaphysician on November 5, 2009 5:09 PM writes...

*cough* Am I the only one who always reads that as "Reversatol" ( pronounced "reverse it all" )?

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13. Kismet on November 5, 2009 5:19 PM writes...

@floyd, Bill Sardi a miracle? yes, for obese and diabetic rats. Not healthy people. Wine on the other hand has been proven to be benefical, but it would be fallacious to attribute its effects to resveratrol or anything else right now (we don't have a clue what it is!)

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14. Anonymous on November 5, 2009 6:16 PM writes...

Actually, resveratrol itself has been enough to activate the "Make-big-molecules pathway in academic synthetic organic chemists." See Snyder et al., Total Synthesis of Resveratrol-Based Natural Products, 46 Angew. Chem. Int. Ed. 8186 (2007), available at http://www.columbia.edu/cu/chemistry/groups/snyder/Manuscripts/ACIE-2007-46-8186.pdf.

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15. Retread on November 5, 2009 6:50 PM writes...

If you want to see how crazy things can get, look at my Chemiotics post of 15 May '08 on "The Skeptical Chymist" titled "Do you know where your drug is (and what it is doing)?" It involves (1) an intracellular second messenger -- ceramide (2) the protein mutated in cystic fibrosis called CFTR (3) amitriptyline, a tricyclic antidepressant which we all know how it works. Except that we don't.

It turns out that CFTR mutations increase the levels of ceramide inside the lungs (the primary site of infection in cystic fibrosis). This is caused by alkalinization of the intracellular sites where ceramide is broken down. Elevated ceramide levels are thought to increase cell death, resulting in lung infection (the bacteria have more to munch on).

Where does amitriptyline fit in? It lowers lung ceramide levels. How? By decreasing the amount and/or the activity of an enzyme (acid sphingomyelinase) which breaks down a precursor of ceramide. The paper is silent on the mechanism(s) by which this happens (but does give two references #24, #25). Treating transgenic mice with mutant CFTR with amitriptyline decreases the frequency and severity of their lung infections. Amazing.

Where does the effect of amitriptyline on neurotransmitter re-uptake fit into all of this? It doesn't, and that's just the point.

There's lots more detail in the post (including literature citations) but this should prevent any of us from getting too cocky about our knowledge of just what drugs and the myriads of endogenous players are doing inside the cell.

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16. cliffintokyo on November 5, 2009 8:08 PM writes...

All posts are *spot on*, but you are missing the elephant......
(deliberately perhaps, Hap and Retread?)
This is a fabulooous opportunity for medicinal chemists to create a potent *clean* analogue of *dirty* resveratrol.

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17. Will on November 5, 2009 10:11 PM writes...

Sirtus/GSK compounds

http://en.wikipedia.org/wiki/SRT1720

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18. SIR T1 on November 5, 2009 10:40 PM writes...

Maybe resveratrol does not act via the SIRT1 pathway but there appear to be advantages of knocking down SIRTi in the liver

SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats
Derek M. Eriona,b,c,1, Shin Yonemitsua,b,1, Yongzhan Nied, Yoshio Nagaia,b, Matthew P. Gilluma,b,c, Jennifer J. Hsiaob, Takanori Iwasakib, Romana Starkb, Dirk Weismannb, Xing Xian Yue, Susan F. Murraye, Sanjay Bhanote, Brett P. Moniae, Tamas L. Horvathd, Qian Gaod, Varman T. Samuelb and Gerald I. Shulmana,b,c,2

PNAS July 7, 2009 vol. 106 no. 27 11288-11293

Permalink to Comment

19. MTK on November 5, 2009 10:49 PM writes...

Are you being facetious cliff and I'm missing the joke?

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20. Jose on November 5, 2009 11:54 PM writes...

"This is a fabulooous opportunity for medicinal chemists to create a potent *clean* analogue of *dirty* resveratrol."

I think one of the biggest lessons from the last 20 year of NP synthesis is that many, many NPs cannot be optimized in med chem fashion. Truncations sometimes work, but in general for molecules like resveratrol which thumb their noses at Lipinski, the observed activity is a global phenomenon that we really can't *begin* to deconvolute.

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21. cliffintokyo on November 6, 2009 12:53 AM writes...

#19 and #20
I started tongue-in-cheek and ended serious.

Serious:
Any non-selective lead needs more interactive groups with the correct spatial orientations to improve selectivity for the desired receptor,
and or conformational restrictions with the same objective in mind.
Design some suitable scaffolds, put in some extra and promising (H-bonding, etc) receptor binding groups (based on likely receptor interactions, where receptor structure is known/ligand receptor binding info is available, or empirically where there is limited info) and hey-presto! we have a med chem project. Start by learning how to synthesise the b---rs, preferably a few months before screening of newly syntheised compounds is initiated. Don't forget to check patents and lit and throw out all the worked out 'design spaces'.

With apologies to all serious medicinal chemists.

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22. Jack on November 6, 2009 7:34 AM writes...

#8...... You are right. Those two are responsible for destroying a great R&D organization. The Sirtis deal is just one example of many, many poor decisions driven by their own personal agendas. GSK is doomed.

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23. K on November 6, 2009 8:23 AM writes...

Tachi bought some cr*p too. His final big deal was a particularly poor effort...

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24. MTK on November 6, 2009 9:12 AM writes...

Cliff,

And exactly what are you going to target here using resveratrol as your lead?

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25. Hap on November 6, 2009 11:18 AM writes...

14: I liked that paper, and at least the molecules were simple enough that they might be useful if they can be made rapidly. TaxolXXXXXpaclitaxel wasn't ever going to be producible in that way, and analogs (other than at the amino acid side chain) were probably not going to be useful either.

I think that resveratrol and its derivs might be useful (and the sirtuins might be useful, too, at least to understand), but buying a company for a lot of money with (apparently) not much understanding of the fundamental biology seems like a problem. Do you think Amgen spent $720M to develop their assays and get useful data on resveratrol? If Amgen was able to develop that capacity, why couldn't GSK? (Part of buying the company - most, I assume - is the IP, but if the IP isn't relevant to the desired activity, well...)

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26. alig on November 6, 2009 1:05 PM writes...

25: Actually GSK had run a screen for Sirt1 inhibitors, but everything they got from the screen turned out to be artifacts. That's why Moncef and Patrick wanted to buy Sirtris, b/c they supposedly had what GSK had been unable to get internally. Unfortunately, Moncef listened to the Sirtris people rather than the GSK scientists who did the due dillegence. That is one of many reasons he should be fired.

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27. Anonymous on November 8, 2009 8:03 PM writes...

#24 MTK

I only described a generic approach to starting and pursuing a med chem project.
I am not an expert on resveratrol and related compounds med chem (altho' I have worked in the antioxidant field in the distant past), and I apologize if I unintentionally gave any other impression.

I tend to agree with other comments that GSK do not appear to have been very diligent in reaching their agreement with Sirtris.
However, who knows what the opportunities might be if GSK is enlightened enough to give their chemists a 'licence' to invent some new compounds.
Have you looked at the structures of some of the prostaglandin analogues that have been reaching the market recently? They don't look much like PGs do they? How long did it take these innovative analogues to get to market; 20 years? Perhaps because of chemists preconceived ideas about SAR? Might have been done in half the time if chemists had been 'free' (willing?) to use their imagination, and ruthless about discarding lead 'scaffolds' that were hopelessly embedded in over-patented 'design space'...

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28. cliffintokyo on November 8, 2009 8:08 PM writes...

#27
Sorry, did not intend post #27 to be anonymous.
Cliff

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29. anon on November 9, 2009 1:05 PM writes...

Why doesnt anyone point out the only thing that matters—the SIRT compounds are active in animals, who cares what the mechanism is? $720M for a >1$B/yr drug sounds like a good deal to me...

Permalink to Comment

30. Hap on November 9, 2009 1:19 PM writes...

Because GSK probably bought the company to get the IP (compounds which inhibit a pathway) - if they don't do that, then the IP isn't worth much, either as a roadblock or as an enablement. Second, the knowledge the company has about resveratrol, et al, doesn't really add up - so they aren't necessarily getting the information and experience they expected to. Finally, GSK would like to have an idea how resveratrol works because the FDA will ask it of any drug they develop. People prescribing it would like to know what drugs it might interfere with both now and in the future, and without any idea of what pathways the drug works on, they're making blind guesses on that. (It's also likely to be harder to make a drug without an assay short of trying it in people, and resveratrol itself is available from too many sources for their testing to be cost-effective - if they can't make money on it, why spend the money to develop it as a drug?) They didn't get any of that - so they could have developed a compound for far less money (perhaps more quickly) without having spent that money on buying Sirtris.

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31. Anonymous on November 9, 2009 7:55 PM writes...

This is just the latest in a long line of papers pointing to the sloppiness or worse of Sinclair and his sirtris buddies in their rush to get rich. Which they did. What I don't understand is why NIH isn't looking into why so much of the data from Sinclair's lab (supported by NIH funds) is turning out to be garbage.

Permalink to Comment

32. David Sinclair on December 6, 2009 12:45 PM writes...

Please keep unwarranted personal attacks out of this productive discussion.

Co-crystal structures explaining assay and mechanism of sirtuin activation by resveratrol are at:
http://twitpic.com/rvtdx

and the full study:
http://en.scientificcommons.org/50784021

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33. Anonymous on February 11, 2010 6:01 AM writes...

Love the post from David Sinclair, I hope that was really him. He links to a picture of a crystal structure on "twitpic" and then the "full study" that is someone's dissertation in German.

HAHAHAHAHAHAHHAHAHAHA!


David, you clown, the reason the discussion has included personal attacks is because you have been exposed as a fraud. This is what happens when you publish bullshit, repeatedly, and then get caught.

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34. Anonymous on February 12, 2010 7:59 PM writes...

I second post #31. The government should investigate Dr. David Sinclair of Harvard Medical School for publication of false data. There is no question about the appearance of wrongdoing here. Multiple papers have now been published directly contradicting Dr. Sinclair's data and it is widely speculated among his colleagues that he "made it up". Dr. Sinclair should welcome the opportunity to clear his name and restore his reputation.

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35. Anonymous on April 1, 2010 11:45 AM writes...

I had worked at Harvard. I saw many people being promoted in the fast track. But David is in the flying track. When people do so good like that for political reason (Harvard system is never short for political), I have no problem. This is our world. When people do so good by their science like David, I have to question their science. Frankly, I never believed in him. When Iheard GSK spend money on it, I first laugh. Then, wondering why GSK not send one to Harvard to ask around how many of use believe in David?

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