SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1

Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS · The Journal of Biological Chemistry

The standing challenge to the SIRT1 activator label, and it tests the claim three ways. Against a p53-derived peptide lacking a fluorophore, and against purified full-length p53 and acetyl-CoA synthetase 1, resveratrol and the three SRT compounds produced no apparent activation of SIRT1; against a peptide carrying a covalently attached fluorophore, all four activated it. NMR, surface plasmon resonance and isothermal calorimetry then showed the compounds binding the fluorophore-containing peptide directly, which supplies a mechanism for the discrepancy rather than only reporting it. In mice on a high-fat diet, SRT1720 neither lowered plasma glucose nor improved mitochondrial capacity. All four compounds showed multiple off-target activities against receptors, enzymes, transporters and ion channels.

Population

Biochemical assays of purified SIRT1 with native peptide and full-length protein substrates (p53, acetyl-CoA synthetase 1), plus an in vivo arm in ob/ob mice on a high-fat diet

Intervention

Resveratrol and the SRT-series compounds tested for direct SIRT1 activation

Comparator

The fluorophore-tagged peptide substrate used in the original activation assays

Limitations

Biochemistry from a Pfizer group, published while the company that developed the SRT compounds was a competitor, which the affiliations disclose. It does not rule out indirect SIRT1 activation in cells through upstream signalling, and a later group argues that hydrophobic motifs in genuine substrates permit activation with no fluorophore involved. The in vivo arm tests SRT1720 rather than resveratrol.