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Feb 16, 2012
 |  BC Innovations  |  Targets & Mechanisms

Still un-sirtuin

Researchers at the NIH have proposed a new mechanism to explain the beneficial metabolic effects of resveratrol, a polyphenol compound from red wine thought by many to act primarily on sirtuin 1. The NIH team suggests resveratrol works by inhibiting phosphodiesterase-4, an enzyme that sits far upstream of sirtuin 1 and affects a signaling pathway that leads to increased energy utilization.1

The findings could provide repurposing opportunities for the plethora of phosphodiesterase-4 (PDE-4) inhibitors on the market or in the clinic, primarily for pulmonary indications.

Prior work by researchers at Harvard University and the Massachusetts Institute of Technology suggested resveratrol promotes the consumption of energy and other antidiabetic effects by activating sirtuin 1 (SIRT1), a protein deacetylase implicated in a variety of metabolic and neurodegenerative processes.2 Indeed, that research led to the formation of Sirtris Pharmaceuticals Inc., which was acquired in 2008 by GlaxoSmithKline plc for $651 million.

In 2010, GSK discontinued development of Sirtris' lead compound, SRT501, after data from an open-label Phase IIa trial in 24 patients showed the orally bioavailable formulation of resveratrol had minimal efficacy and increased the risk of renal complications in patients with multiple myeloma (MM).

The pharma's next-generation SIRT1 activator, SRT2104, has completed Phase II testing for type 2 diabetes and is in Phase I testing for cardiovascular and inflammatory indications. GSK has at least two other SIRT1 activators in Phase I testing in inflammatory indications.

While the molecules were moving through the clinic, independent teams at several academic institutions and at Elixir Pharmaceuticals Inc., Amgen Inc. and Pfizer Inc. reported that, in their hands, resveratrol and three other Sirtris compounds, not including SRT2104, did not directly activate SIRT1 in vitro.3-6

"The question is how can these compounds activate SIRT1 if they don't directly activate it," said Jay Chung, chief of the Laboratory of Obesity and Aging Research at the NIH's National Heart, Lung, and Blood...

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