Abstract

Drug Discovery Meet 2020- SIRT6 small molecule modulator as a potential anti-inflammatory treatment for targeting TNF-ɑ related disorders

SIRT6 is a NAD+ dependent deacylase enzyme with a key role in ageing, metabolism and  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 Histone 3 K9. Therefore, SIRT6 modulators could become future anti-inflammatory drugs for treating TNF-ɑ related disorders. In order to inhibit TNF-ɑ secretion, we aimed to modulate specifically SIRT6’s deacylation activity. We characterized SIRT6 activity and physical interaction with small compounds using a pipeline of in-vitro and in-silico assay systems. As a result, 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.


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