Sirtuin inhibitors

Background: The sirtuin family of deacetylase enzymes comprises seven proteins (SIRT1-7) that are dependent on NAD+ for their activity. Three proteins are located in the nucleus, three in the mitochondria and only one is predominantly cytoplasmic. Caloric restriction and oxidative stress generally up-regulate their expression. SIRT1, the orthologue of yeast Sir2, is the mammalian sirtuin that has been most extensively studied to date. Among other targets, SIRT1 down-regulates the activity of the nuclear transcription factor p53, being this related with an increase in lifespan and cell survival associated to stress resistance. Objective: Because sirtuin modulation could have beneficial effects on several human diseases, there is a growing interest in the discovery and development of small molecules that modify its activity. This review will be focused on sirtuin inhibitors. Conclusions: Several specific inhibitors of SIRT1 have been described. These compounds could be mainly useful for the treatment of cancers by increasing p53 activity that stops the formation of tumours and induces apoptosis. A p53-independent massive induction of apoptosis has been also described for one inhibitor. In addition, a potent and selective SIRT2 inhibitor that ameliorates the a-synuclein fibril formation in Parkinson disease has been proposed to treat this kind of neurodegenerative disease.