Sirtuin modulators: past, present, and future perspectives

Abstract

Sirtuins are NAD⁺-dependent protein lysine deacylase and mono-ADP ribosylases present in both prokaryotes and eukaryotes. The sirtuin family comprises seven isoforms in mammals, each possessing different subcellular localization and biological functions. Sirtuins have received increasing attention in the past two decades given their pivotal functions in a variety of biological contexts, including cytodifferentiation, transcriptional regulation, cell cycle progression, apoptosis, inflammation, metabolism, neurological and cardiovascular physiology and cancer. Consequently, modulation of sirtuin activity has been regarded as a promising therapeutic option for many pathologies. In this review, we provide an up-to-date overview of sirtuin biology and pharmacology. We examine the main features of the most relevant inhibitors and activators, analyzing their structure-activity relationships, applications in biology, and therapeutic potential.

Keywords: aging; cancer; drug discovery; epigenetics; metabolism; neurodegeneration; protein lysine deacylation; sirtuin modulators; sirtuins.

Figure 1.. Sirtuins: similar catalytic mechanism but different sequences.

(A) Schematic representation of the deacylation reactions catalyzed by sirtuins. (B) Sirtuins amino acid sequence alignment. The N-terminal domain is represented in orange, the C-terminal domain in blue, and the catalytic domain in yellow.

Figure 2.. Selisistat, its derivatives and its binding mode to hSIRT1.

(A) Structures of Selisistat (S–1a) and its derivatives 1b–d with relative sirtuin inhibition data. (B) x-ray crystal structure of hSIRT1 catalytic domain in complex with CHIC-35 (S-1b; PDB ID: 4I5I) [75]. (C & D) Details of SIRT1/S-1b interactions showing the hydrogen bonds with Q345, I347, D348 and conserved water molecules. SIRT1 is colored in green with selected residues shown as white sticks, S-1b is represented as yellow sticks, NAD⁺ is represented as cyan sticks, the hydrogen bonds in which S-1b is involved are represented as magenta dotted lines, the hydrogen bonds in which NAD⁺ is involved are represented as orange dotted lines, water molecules are represented as red spheres, Zn²⁺ is represented as a dark sphere.

Figure 3.. Structures and enzymatic activities of SIRTi of SIRTi 2–7.

(A) SIRTi 2–3. (B) Salermide (4a) and its related compounds (4b–g). (C) SIRTi 5–7.

Figure 4.. Structures and enzymatic activities of SIRTi 8–14.

(A) Nicotinamide-based SIRT2-selective derivatives (8–10). (B) The thiomyristoyl lysine derivative TM (11a), its analogues 11b–d and 12a–d. (C) SirReal2 (13a) and its derivatives (13b–e, 14a, 14b).

Figure 5.. Structures and enzymatic activities of SIRTi 15-22.

(A) SIRT3i 15 and 16. (B) SIRT5i 17–19. (C) SIRT6i 20–21 and SIRT7i 22.

Figure 6.. Sirtuin activators.

(A) Structures and enzymatic activities of SIRT1a 23–24. (B) Structure of STAC 24h and x-ray crystal structure of mini-hSIRT1 in complex with 24h (PDB ID: 4ZZH) [194] with details showing the hydrogen bond with N226 and the hydrophobic interactions with surrounding residues. Mini-hSIRT1 is colored in green with selected residues shown in white sticks, 24h is represented as yellow sticks, the hydrogen bond is represented as a magenta dotted line, Zn²⁺ is represented as a dark sphere. (C–D) Structures and enzymatic activities of DHP-based SIRTa 25a–d (C) and SIRT6a 26–28 (D).