SIRT6 small molecule modulator as a potential anti-inflammatory drug for treating TNF- α related disorders

SIRT6 is a NAD⁺ dependent deacylase enzyme with a key role not only in ageing and metabolism, but also in inflammation. Chronic inflammation conditions are often characterized with uncontrolled Tumor Necrosis Factor Alpha (TNF-ɑ), cytokine production. Dysregulation of TNF-ɑ has been implicated in a variety of human diseases including inflammatory bowel disease, Alzheimer`s disease, Amyotrophic lateral sclerosis and more. SIRT6 has a dual role in TNF-ɑ inflammatory pathways. SIRT6 can control TNF-ɑ secretion levels by a removal of a myristoyl group from TNF-ɑ K19. Upon deacylation, TNF-ɑ is localized to the cell membrane. If stayed acylated, it is more tended to be degraded by the cell lysosome. After secreted, TNF- ɑ enhancing the inflammatory response in target cells by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). On the other hand, SIRT6 regulates transcription factor NF-kB by deacetylating H3K9. Therefore, SIRT6 modulators could become future anti-inflammatory drugs for treating TNF- ɑ related disorders. In order to modulate TNF- ɑ secretion, we aimed to characterize SIRT6 activity and physical interaction with NAD⁺, acylated substrates and new small compounds using pipeline of in-vitro and in- silico assay systems. Using biochemical, biophysical and cellular based assays we were able to identify a novel small compound with the ability to modulate TNF-ɑ secretion. Therefore, we suggest this compound as a starting candidate in order to develop new anti-inflammatory drugs.