Differential modulation of SIRT6 deacetylase and deacylase activities by lysine-based small molecules

• DOI: 10.1007/s11030-019-09971-2
• Publication Date: 2019-06-25T13:12:50Z
• Authors: Giovanna Sociali; Nara Liessi; Alessia Grozio; Irene Caffa; Marco Daniele Par...; Silvia Ravera; Bruno Tasso; Andrea Benzi; Alessio Nencioni; Alberto Del Rio; Inmaculada Robina; Enrico Millo; Santina Bruzzone
• Keywords: Small Molecule Libraries; 0301 basic medicine; 03 medical and health sciences; Molecular design; Tumor Necrosis Factor-alpha; Drug Design; Lysine; Sirtuins; Small molecule SIRT6 modulators; Enzyme Inhibitors; Molecular design; Sirtuins; Small molecule SIRT6 modulators

Sirtuin 6 (SIRT6) is an NAD+-dependent deacetylase regulating important functions: modulators of its enzymatic activity have been considered as possible therapeutic agents. Besides the deacetylase activity, SIRT6 also has NAD+-dependent deacylase activity, whereby it regulates the secretion of cytokines and proteins. We identified novel SIRT6 modulators with a lysine-based structure: compound 1 enhances SIRT6 deacylase while inhibiting the deacetylase activity. As expected based on the biological effects of SIRT6 deacetylase activity, compound 1 increased histone 3 lysine 9 acetylation and the activity of glycolytic enzymes. Moreover, the fact that compound 1 enhanced SIRT6 deacylase activity was accompanied by an increased TNF-α release. In conclusion, new SIRT6 modulators with a lysine-like structure were identified, with differential effects on specific SIRT6 activities. The novel SIRT6 modulator concomitantly inhibits deacetylase and enhances deacylase activity.