New sirtuin modulators: their uncovering, pharmacophore, and implications in drug discovery

Sirtuins are a group of enzymes known as class III histone deacetylases that catalyze the deacetylation reaction and are presented across various species. In humans, they exhibit seven isoforms known as SIRT1–7, localize in distinctive cellular compartments, the nucleus (SIRT1, 6, 7), cytoplasm (SIRT2), and mitochondria (SIRT3, 4, 5). They play crucial roles in metabolism, DNA repair, and rRNA transcription. As research on sirtuins has expanded, there has been increased interest in identifying sirtuin modulators that may hold therapeutic implications in various diseases. Despite the identification of numerous sirtuin modulators, only few have entered clinical trials due to selectivity and safety concerns. Hence, subsequent research is needed to understand their mechanisms and ensure their safety profiles. This review summarizes experimental data and the status of sirtuin modulators reported from 2013 to current, aiming to contribute to the advancement of sirtuin modulation research and the identification of promising candidates for future development.