Sirtuin Modulators: Targets for Metabolic Diseases and Beyond

Abstract

Over the past ten years, sirtuins have emerged as an important class of drug targets. These enzymes play an important role in gene activation and silencing in all organisms from prokaryotes to humans. There is evidence that sirtuin modulation can be beneficial for a wide variety of diseases associated with aging. Among these conditions are diabetes, neurodegenerative diseases, and cancer. Agents that activate some sirtuins may be beneficial, while inhibitors of other sirtuins might represent treatment options. This review covers the chemical activators and inhibitors of the sirtuins that have appeared in the literature through the first half of 2008.

Anti-Trypanosoma cruzi activity of nicotinamide

“…The residues Asp 98 presents strong intermolecular hydrogen bonds with the carboximide moiety, which functions as an anchor to fix nicotinamide in the C pocket. The positioning of nicotinamide in the C pocket and the rotation of the carboxamide group are comparable to what has been observed in the structure of Sir2Af2 bound NAD + in the "productive" conformation (Szczepankiewicz and Ng, 2008).…”

“…The catalyzed deacetylation conducts to production of 2 -and 3 -O-acetyl-ADP-ribose and deacetylated lysine. If nicotinamide binds to the enzyme when it contains the O-akyl-amidate intermediate, nicotinamide can react with the intermediate in a procedure known as nicotinamide exchange, in which NAD + and N6-acetyl-lysine are reformed (Szczepankiewicz and Ng, 2008;Taunton et al, 1996;Thomsen and Christensen, 2006;Timmers et al, 2008). Furthermore, the rate of the nicotinamide exchange reaction can be increased by raising the nicotinamide concentration, which happens at expense of the deacetylation activity.…”

Functional dissection of SIRT6: Identification of domains that regulate histone deacetylase activity and chromatin localization

“…Our data demonstrating functional roles for the N- and C-terminal extensions of SIRT6 suggest that these domains may serve as sites of regulation, for example, through post-translational modification (North and Verdin, 2007b) or interactions with yet-to-be-identified SIRT6 regulatory factors. Furthermore, because chromatin-modifying enzymes are highly amenable to small molecule regulation, SIRT proteins are actively being pursued as pharmacological targets for metabolic disorders, age-related diseases, and cancer (Lavu et al, 2008; Szczepankiewicz and Ng, 2008; Westphal et al, 2007). In this context, deciphering the structural determinants of SIRT6 enzymatic activity—both in vitro and in cells—should be valuable for improving the design of small-molecule modulators.…”

Small-Molecule Allosteric Activators of Sirtuins

“…These scaffolds include benzimidazoles, thiazolopyridines, and urea-based scaffolds (80–83). Medicinal chemistry has generated thousands of analogs of these scaffolds, which can be up to three orders of magnitude more potent than resveratrol (84). It has been a conundrum that such a diverse set of small molecules can activate SIRT1 but not SIRT2–7, but we believe that this issue has recently been resolved, as described below.…”