Discovery of novel SIRT5 activators as potential anti-inflammatory agents

NAD⁺-dependent class-III histone deacetylases (HDACs), also known as sirtuins (SIRTs), comprise seven isoforms (SIRT1-7) that play key roles in maintaining cellular functions, regulating metabolic and homeostatic processes, and preventing oxidative stress damage. SIRT5 is located in the mitochondrial matrix (along with SIRT3, which shares some of its activities, and SIRT4). This isoform regulates the metabolism of ammonia, the tricarboxylic acid cycle (TCA), glycolysis, fatty acid oxidation, apoptosis, and the electron transport chain. Considering the potential of SIRT5 as a pharmacological target, several modulators, acting as both sirtuin-activating (STACs) and sirtuin-inhibiting compounds (STICs), have been published. SIRT5 deficiency is known to increase the severity of rheumatoid arthritis in rat model; so, its activation may exert an anti-inflammatory role. On this basis, we decided to focus our efforts on SIRT5 STACs, since only few selective SIRT5 activators have been reported in the literature so far.

In an attempt to identify novel anti-inflammatory agents, we considered the repositioning of several compounds belonging to our in-house library, also including some furan derivatives, active as antitubercular agents.

The compounds were screened by a SIRT5 promoter assay, and their SIRT5 desuccinylation activity was evaluated. Some of them showed interesting properties as SIRT5 activators and, most notably, no cytotoxic activity. The preliminary results of our ongoing studies will be presented.