Julien, te la ricordi la discussione con funes riguardo a Sinclair e alla Sirtris? funes sospettava ci fosse molto fumo e niente arrosto, soprattutto considerando le cifre in gioco (Glaxo).
Si mettano l'anima in pace quanti hanno buttato via soldi o speranze mal riposte nel resveratrolo, un inutile e costoso pesticida.
Leggiti questo:
http://pipeline.corante.com/archives/2010/01/12/the_sirtris_compounds_worthless_really.php
The Sirtris Compounds: Worthless? Really?
Posted by Derek
As followers of the drug industry know, GlaxoSmithKline famously paid $720 million to buy Sirtris Pharmaceuticals in 2008. Sirtris is the most high-profile shop working on sirtuins and resveratrol-like pharmacology, which subject has received a massive amount of press (some accurate, some scrambled). I've been following the story with interest, since the literature has me convinced that the aging process can indeed be modified in a number of model organisms, which makes me think that it could be in humans as well. And I also feel sure that advances in this area could lead to many profound medical, social, and economic effects. (GSK, though, is going after diabetes first with the Sirtris deal, I should add - among other reasons, the FDA has no regulatory framework whatsoever for an antigeronic, if I can coin a word.)
But whatever the state of the anti-aging field, doubts have crept in about the wisdom of the Sirtris purchase. Last fall, a group at Amgen published a study suggesting that some of the SIRT1/resveratrol connections might be due an an experimental artifact caused by a particular fluorescent peptide. Now a group at Pfizer has piled on in the Journal of Biological Chemistry. They're looking over resveratrol and a series of sirtuin activators described by the Sirtris group in Nature.
And unfortunately, they also find trouble due to fluorogenic peptides. The TAMRA fluorophore on their peptide substrates seems to pervert the assay. While the Sirtris compounds looked like activators initially, switching to the native peptide substrates showed them to be worthless. Further study (calorimetry) showed that the activator compounds bind to a complex of SIRT1 and the fluorescent peptide substrate, but not to SIRT1 itself (or in the presence of native substrate without the fluorogenic group). That's not good.
But worse is to come:
Despite a lack of evidence for the Sirtris series of compounds as direct SIRT1 activators, we investigated whether the in vivo efficacy demonstrated by SRT1720 in several rodent models diabetes could be validated and attributed to indirect activation of SIRT1. We therefore attempted to reproduce the in vivo efficacy for SRT1720 in mouse models of type 2 diabetes previously shown. . .
That word attempted should tell you what comes next. The reported high dose of the compound (100 mpk) resulted in weight effects and death. The reported low dose (30 mpk) showed no effects at all on any diabetic parameters, but instead seemed to lead to increased feeding and weight gain. To complete the debacle, the Pfizer group screened the Sirtris compounds through a broad panel of assays, and found that all of them hit a number of other targets (and appear significantly worse than resvertarol itself, which is no one's idea of a clean compound to start with).
Basically, these folks have thrown down the gauntlet: they claim that the reported Sirtris compounds do not do what they are claimed to do, neither in vitro nor in vivo, and are worthless as model compounds for anything in this area of study. So what is GSK going to have to say about this? And what, if this paper is at all accurate, did they buy with their $720 million?
e questo:
http://pipeline.corante.com/archives/2010/01/25/gsk_and_sirtris_a_bit_more.php
GSK and Sirtris: A Bit More
Posted by Derek
Nature has a short item on the Pfizer paper that questions the reproducibility of some key sirtuin work (covered here and here). There are some good points to temper the pessimism. Leonard Guarente of MIT, a key pioneer in the field, says:
. . . that the latest findings are neither surprising nor worrisome. The compounds may work only with fluorophore-conjugated peptides in vitro, says Guarente, but the situation is different in cells and in animals. The Nature paper, among others, went beyond the test tube and indicated that SIRT1 was more active in cells and in animals after application of the Sirtris compounds. Furthermore, resveratrol administration made no difference to the lifespan of yeast that did not have Sir23, indicating that the compound's action depends on this gene.
According to a statement from GlaxoSmithKline, Ahn's conclusion ignores any possibility of direct activation of SIRT1 that may occur in a cellular environment that is not reproduced in vitro.
True, but there's still that problem of the Pfizer group not being able to reproduce the in vivo effects, which to me was perhaps the most worrisome part of the paper. Now, it's worth remembering that animal studies are not the easiest things in the world to do right, since there are so many variables. Small differences in animal strains and the like can sometimes throw things off severely. Even the Pfizer group admits this readily, with Kay Ahn telling Nature that every in vivo experiment is a little bit different and that Under our conditions we didn't see beneficial effects, but we don't want to make a big conclusion out of those results.
That's an honorable way to put things, I have to say. Rather less honorable, though, at least to me, is David Sinclair's response from the Sirtris team. See what you think:
A possible explanation for the discrepancy, says Sinclair, is that Ahn and her colleagues did not provide information on the characterization of the compounds, which they synthesized themselves. So there is no way of knowing how pure they were or whether they're the same as those made by Sirtris. The fact that mice died indicates that there may be an issue with purity,
.
That's. . .not so good. In fact, it comes close to being insulting. Although I say a lot of uncomplimentary things about Pfizer's management, the fact remains that they have a lot of very good scientists there. And I assume that they can reproduce Sirtris's published procedures to make the sirtuin ligands. If they can't, frankly, that's Sirtris's fault. Everyone (well, everyone competent) checks out compounds thoroughly before putting them into an animal study. Asking Are you sure you made the right stuff? at this point is really a bit much, and doesn't do anything improve my opinion of Sirtris. (Which opinion actually was pretty good - until recently).
e questo: http://pipeline.corante.com/archives/2010/01/15/sirtuin_scenarios.php
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