Design of Novel Molecules that Regulate Sirtuins
Researchers at The Wistar Institute have identified and characterized a novel target binding site involved in regulating the activity of Sir2 proteins (or Sirtuins, the class III family of histone deacetylases, silent information regulator 2). Sirtuins deacetylate numerous cell proteins, thereby stimulating diverse biological functions related to metabolism and cell growth. Their activity has been linked to increased lifespan and calorie-associated effects on longevity. Compounds that target Sirtuins show promise in the treatment of diabetes, and diseases of degeneration and aging. Wistar scientists have identified and characterized a new molecular binding target, the nicotinamide binding site, which is expected to enable the development of new classes of small molecule Sirtuin modifiers. Experimental studies have validated the role of this binding site in the regulation of Sirtuin activity. Small-molecule compounds that target this site can act either as inhibitors of Sirtuins, or as effective Sirtuin activators, influencing a range of biological functions including DNA regulation, programmed cell death, neuronal protection, insulin signaling, and fat mobilization.