Sirtuins as drug targets

The mammalian sirtuins (SIRTs) are evolutionally highly conserved proteins and belong to class III histone deacetylases (HDACs). Its seven family members (SIRT1–7) share a NAD+-dependent catalytic protein lysine deacetylase and/or mono-ADP-ribosylase mechanism and are involved in various biological processes acting on diverse substrates. SIRTs vary in length and sequence at their N- and C-termini. This might explain in part their diverse functions and localizations. To date, their protein lysine deacetylation is the most studied function; however recent studies revealed that several SIRTs also are able to cleave other types of acyl groups, e.g. succinyl, malonyl, glutaryl, and long-chain fatty acyl residues . In recent years, there is a growing body of literature highlighting the association of SIRTs with various pathologies: SIRT inhibition might be beneficial in cancer treatment, viral infections, muscular diseases, and neurodegenerative disorders, whereas SIRT activationmay have a positive impact onmetabolic and age-related disorders.Thus, the discovery of SIRT modulators via screening of chemical libraries and catalytic mechanism-based design approaches, often in combination with structure–activity relationship (SAR) investigations, is nowadays a field of active research. In this book chapter, wewould like to illustrate themost important SIRT functions and SIRT modulators discovered so far.