US biotech unveils drug leads 1000 times more potent than resveratrol, found in red wine
A US biotechnology company has identified compounds that mimic the health benefits of a component in red wine - but are 1000 times more effective.1 Researchers from Sirtris Pharmaceuticals of Cambridge, Massachusetts say that their synthetic compounds could offer a new treatment for type II diabetes without the risks associated with drinking wine every day.
The natural polyphenol resveratrol, found in the skin of black grapes, has been found to ameliorate the damage caused by a fatty diet. Both resveratrol and the chemically unrelated compound made by Sirtris appear to act by activating the SIRT1 enzyme pathway that is key to the body’s response to a low energy diet.
Scientists have known that calorie restriction has positive effects on general health since the 1930s. In species as diverse as nematode worms, fruit flies and rats, it slows down many of the processes associated with ageing and can extend life expectancy by up to 30 per cent.
Sirtris chief executive Christoph Westphal and colleagues compared the effects of a number of compounds given to mice made obese by either a genetic abnormality or a high fat diet and to a mutant strain of rats which, like human type II diabetics, have abnormal insulin metabolism.
After about four weeks treatment with one of them - SRT1720 - there were significant improvements in the animals’ response to insulin, reduced blood glucose levels and an increase in the number and activity of mitochondria in their cells. Reductions in the efficiency of mitochondria - the cellular organelles involved in energy metabolism - have been identified in many diseases associated with ageing, including type II diabetes. The other compounds (SRT1460, SRT2183) had similar but less pronounced effects. All three were also roughly 1,000 times better than resveratrol at activating SIRT1.
Westphal is confident that the effects seen in laboratory animals will also be found when the compound is used in people. ’These three rodent models are the gold standard in diabetes research. Our compound has been found to lower glucose and increase insulin sensitivity in each of them and most people would say that is highly predictive of the effects in human diabetics,’ Westphal told Chemistry World.
Evidence to back up this claim should be available before the end of the year when the company expects to report the results of preliminary safety trials in humans on its proprietary oral formulation of resveratrol. It has already begun human trials on the synthetic SIRT1 activator and expects the results to be available during the first half of 2008. If it is successful, the synthetic drug would be given as a daily 100mg oral dose, compared with the 2.5-5g of resveratrol required to achieve the same effects.
However, other researchers in the field told Chemistry World that the metabolic effects of a restricted calorie diet are more complicated than Sirtris is claiming.
’Their data is consistent with the idea that activators of SIRT1 can mimic at least some effects of dietary restriction, but another lab.2 [led by Leonard P Guarente of the Massachusetts Institute of Technology] has published work showing that these same effects of dietary restriction do not require SIRT1,’ said Matt Kaeberlein of the department of cellular and molecular biology at Washington State University. ’Obviously, the most critical questions for human health are whether these compounds will have similar effects in people and, if so, whether activating SIRT1 will have any negative side-effects.’
Nir Barzilai, director of the Institute of Ageing Research at the Albert Einstein College of Medicine, New York agreed that the study doesn’t reveal the whole picture. ’Some of the question remaining are these - are all effects of resveratrol are all through activating SIRT1, or does it have additional effects? And does this drug have effects on aging and other age-related diseases beyond those on glucose homeostasis?’
1 JC Milne et al.Nature450 2 D Chen et al, Science310
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