Two new twists on resveratrol

A couple of significant developments in the resveratrol story occurred this week, but so far the media has focused only on the less important one of the two. I’ll get to the truly important news in a moment. First, here’s the story that hit the wires yesterday: The Healthy Lifespan Institute, a nonprofit cofounded by former Sirtris Pharmaceuticals CEO Christoph Westphal to sponsor research on the red-wine ingredient’s health benefits, announced that it would sell resveratrol supplements “at-cost” for $540 for a year’s supply.

That was especially intriguing since Sirtris, purchased by GlaxoSmithKline for $720 million in 2008, had several years ago developed a similar resveratrol offering, called SRT501, and launched clinical trials with it as a treatment for diabetes and other diseases of aging. SRT501 was regarded as a “proof-of-concept” drug that would demonstrate the therapeutic potential of activating the SIRT1 enzyme—various studies, including those by Sirtris cofounder David Sinclair, a Harvard Medical School professor, have suggested that resveratrol exerts anti-aging effects resembling those of calorie restriction by stimulating SIRT1. But Sirtris’s main thing from the get-go was to develop more potent SIRT1 activators, called STACs (SIRT1 activating compounds) that unlike resveratrol, which affects many molecular targets in cells, would specifically target SIRT1.

As detailed in my book, Westphal, while CEO at Sirtris before the Glaxo acquisition, had considered developing SRT501 as a dietary supplement rather than as a prescription drug. But he’d put the idea on hold for various reasons, including the fact that selling SRT501 as a supplement would have made it impossible for Sirtris to offer it as a high-margin prescription drug if it proved effective in clinical trials.

As I also reported in the book, Glaxo executives were never very interested in SRT501—since resveratrol is a natural substance, SRT501 couldn’t be developed as a lucrative proprietary drug protected by “composition of matter” patents. Thus, after Glaxo purchased Sirtris, it seemed that SRT501 might wither on the vine as the big pharma company focused its SIRT1-related efforts on Sirtris’s novel, proprietary STACs.

The decision by Westphal and Michelle Dipp, another former Sirtris executive who cofounded the Healthy Lifespan Institute, to offer resveratrol supplements via the institute would effectively have infused new life into a SRT501-like nutraceutical. (I haven’t yet reached Westphal and Dipp, though, to ask about the thinking behind their decision.) But shortly after Xconomy broke the story about the nonprofit’s resveratrol sales, TheStreet reported that Glaxo had ordered the two to drop the idea of offering the supplements via the institute, and that both would resign from the institute’s board. (Westphal and Dipp both still hold positions at Glaxo overseeing its investments in external biotechs.)

TheStreet suggested that Glaxo is worried that the nonprofit’s sales of a resveratrol supplement would undermine its “investment in resveratrol drug research.” I seriously doubt that that’s the case, though, especially in light of the second, more important development this week about drugs that activate SIRT1. To wit: A study just out in the Journal of Biological Chemistry has shed new light on the controversy about how Sirtris’s STACs work, and in particular on lingering questions about whether they induce beneficial effects in mammals by directly activating the SIRT1 enzyme. The study also suggests that a Pfizer team drew erroneous conclusions about SIRT1 activators in earlier research that Sirtris’s critics have often cited as evidence that the biotech’s drug program is flawed and that Glaxo blundered when it bought Sirtris.

The controversy, as noted in my recent two-part blog on resveratrol, began in 2005 when back-to-back studies appeared in the Journal of Biological Chemistry (JBC) indicating that resveratrol doesn’t directly activate SIR enzymes as suggested by Sinclair’s earlier studies, which had generated excitement about the compound’s potential to induce the anti-aging effects of calorie restriction. The two earlier JBC studies, as did the Pfizer study, which appeared in JBC in January, called into question Sinclair’s theory that SIRT1 activators like resveratrol interact with SIR enzymes to rev up their removal of acetyl groups from protein substrates—such deacetylation was thought to be SIRT1’s main way of making things happen in cells.

According to the skeptics, Sinclair and his allies at Sirtris had been fooled by a test-tube artifact involving fluorescent molecules they had used to register the SIRT1 enzyme’s activity level. (Sinclair’s team had originally used a fluorescent assay dubbed Fluor de Lys to detect signs that resveratrol amps up the SIRT1 enzyme, and Sirtris had identified its more potent SIRT1 activators with an assay based on a fluorescing molecule called TAMRA.) The skeptics’ data indicated that STACs only stimulate SIRT1’s activity when the assay’s fluorescent molecules are in the mix. That implied STACs probably don’t activate SIRT1 in living cells, whose enzyme substrates obviously don’t include synthetically attached fluorescent tags used for in vitro assays. And that, in turn, suggested to the skeptics that Sirtris’s proprietary STACs were basically worthless, and that Glaxo had been bamboozled.

But there was another way to interpret what was going on: As first suggested by the University of Wisconsin’s John Denu in 2005, it was possible that the fluorescent molecules mimic the action of cells’ natural molecules, or parts of molecules, that happen to combine forces with STACs in cells to rev up SIRT1. If that were true, the apparently misleading fluorescent assays would, by an odd coincidence, have yielded valid indications of STACs’ potential to activate SIRT1 in vivo. One of the attractions of this idea is that it could explain why various studies in living cells and rodents have indicated that Sirtris’s proprietary STACs really do act on SIRT1 to induce health- and longevity-promoting effects.

The latest study by the Sirtris group indicates that Denu was basically right. Importantly, their data shows for the first time that STACs can rev up SIRT1’s enzymatic activity with no fluorescent molecules in the mix.

Based on experiments involving two dozen STACs, the Sirtris researchers also showed that STACs’ ability to stimulate SIRT1 is highly dependent on the molecular structure of the enzyme substrates that are deacetylated by SIRT1—certain “ring systems” in the substrates’ structures apparently enable STACs to rev up SIRT1. In fact, the researchers showed that some purported STACs, whose stimulation of SIRT1 had been suggested by the fluorescent assays, in some cases actually inhibit SIRT1 removal of acetyl groups from substrates whose structures don’t contain such ring systems.

Further, Sirtris’s data suggests that when STACs work to speed up SIRT1, they directly interact with the enzyme to induce a change in the shape of either the SIRT1 enzyme itself, or in the molecular “complexes” that it forms with substrates when shaving acetyl groups from them. This shape, or conformational, change is responsible for the speeding up of SIRT1’s activity. Such “allosteric” mechanisms of action, the Sirtris team observed, are known for modulators of various other enzymes whose action, like SIRT1’s, appears to be highly dependent on their various substrates’ structure.

The Sirtris study didn’t blow away all the fog surrounding STACs’ mechanism of action. Perhaps the biggest remaining mystery is the identify of the thingamabob in cells that interacts with STACs and SIRT1 to help boost the enzyme’s activity in the way that the fluorescent tags do in test-tube assays. One strong candidate is a molecule called DBC1, which a recent study showed is a major regulator of SIRT1’s activity in cells. But SIRT1’s activity is thought to be affected by a number of other modulators in cells, and thus totally eliminating the murk about its mechanism probably won’t be easy.

In any case, the new JBC study adds compelling evidence that Glaxo/Sirtris’s development of proprietary STACs makes sense, and that Glaxo did indeed acquire a host of potentially very valuable SIRT1 activators when it bought Sirtris. The new news on STAC mechanism also suggests that there’s less reason than ever for Glaxo to invest heavily trying to develop SRT501 as a prescription drug—the proprietary STACs are clearly where the action is on SIRT1 activation. What that means for SRT501’s fate remains to be seen, but I seriously doubt that Glaxo feels that its drug-development program at Sirtris is threatened by sales of resveratrol supplements at this point, regardless of who’s selling them.

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