Current Trends in Sirtuin Activator and Inhibitor Development

Abstract

Sirtuins are NAD⁺-dependent protein deacylases and key metabolic regulators, coupling the cellular energy state with selective lysine deacylation to regulate many downstream cellular processes. Humans encode seven sirtuin isoforms (Sirt1-7) with diverse subcellular localization and deacylase targets. Sirtuins are considered protective anti-aging proteins since increased sirtuin activity is canonically associated with lifespan extension and decreased activity with developing aging-related diseases. However, sirtuins can also assume detrimental cellular roles where increased activity contributes to pathophysiology. Modulation of sirtuin activity by activators and inhibitors thus holds substantial potential for defining the cellular roles of sirtuins in health and disease and developing therapeutics. Instead of being comprehensive, this review discusses the well-characterized sirtuin activators and inhibitors available to date, particularly those with demonstrated selectivity, potency, and cellular activity. This review also provides recommendations regarding the best-in-class sirtuin activators and inhibitors for practical research as sirtuin modulator discovery and refinement evolve.

Keywords: drug development; epigenetics; lysine deacylation; sirtuins.

Figure 1

Primary cellular localization and acyl-lysine substrate specificities of human sirtuins. The seven human sirtuin isoforms are differentially distributed between the nucleus (Sirt1, Sirt6, and Sirt7; blue), cytoplasm (Sirt2; white), and mitochondria (Sirt3, Sirt4, and Sirt5; green) and possess distinct acyl-lysine substrate specificities. * = sirtuin deacylase activity confirmed in cells.

Figure 2

General structure of a human sirtuin deacylase bound to an acylated substrate and co-substrate NAD⁺. Key structural domains include the acylated substrate binding cleft (red), the NAD⁺ co-substrate binding pocket (purple), and the zinc-tetrathiolate domain (green). Within and proximal to the NAD⁺ binding pocket, subregions involved in binding the adenine moiety (A-site), the nicotinamide ribose moiety (B-site), and the nicotinamide ribose moiety upon acyl-substrate binding (C-site) of NAD⁺, as well as the extended C-site (EC) and selectivity pocket (SP) exploited by some sirtuin modulators, are outlined by dashed circles and annotated with the corresponding letters. The sirtuin-activating compound (STAC)-binding domain (SBD; blue) is unique to Sirt1. PDB ID: 4ZZJ [39].

Figure 3

Human sirtuins have variable N- and C-termini and catalytic cores. Linear representation of Sirt1-7, with tan denoting the catalytic core. Boundaries of the catalytic core were determined from UniProt for each sirtuin isoform.

Figure 4

Nicotinamide biomolecules are endogenous regulators of sirtuin deacylation. Structures of key nicotinamide-based biomolecules implicated in sirtuin activity.

Figure 5

The sirtuin catalytic mechanism provides a rationale for using thioacyl-lysine derivatives as sirtuin inhibitors. (A) Mechanism of nicotinamide-mediated sirtuin inhibition. (B) Native sirtuin catalytic mechanism with acetylated peptide substrate, yielding 2′-O-acetyl-ADP-ribose and the deacetylated peptide substrate. (C) Stalled sirtuin catalytic mechanism with thioacetylated and thiourea substrates substituted for the acetylated substrate. (D) Thiourea-lysine sirtuin inhibitors. From left to right, Sirt5 inhibitor Compound 49 (a succinyl-thiocarbamoyl pseudopeptide) [201], and Sirt5 inhibitor NRD167 (a succinyl-thiocarbamoyl pseudopeptide) [202].

Figure 6

Peptide lariats represent a novel class of peptidic non-mechanism-based sirtuin inhibitors. Peptide lariat Compound 41 [241].