Sirtuin activators and inhibitors: Promises, achievements, and challenges

Abstract

The NAD⁺-dependent protein lysine deacylases of the Sirtuin family regulate various physiological functions, from energy metabolism to stress responses. The human Sirtuin isoforms, SIRT1-7, are considered attractive therapeutic targets for aging-related diseases, such as type 2 diabetes, inflammatory diseases and neurodegenerative disorders. We review the status of Sirtuin-targeted drug discovery and development. Potent and selective pharmacological Sirt1 activators and inhibitors are available, and initial clinical trials have been carried out. Several promising inhibitors and activators have also been described for other isoforms. Progress in understanding the mechanisms of Sirtuin modulation by such compounds provides a rational basis for further drug development.

Keywords: Activation; Deacetylase; Deacylase; Drug discovery and development; Inhibition.

Figure 1. Potential therapeutic applications for Sirtuin activating compounds (STACs) and Sirtuin inhibiting compounds (STICs)

Chemical structures for examples of activators and inhibitors for Sirt1 and Sirt6 as isoforms with examples for prospective therapeutic applications.

Figure 2. Sirtuin structure, catalytic mechanism, and activation

(a) Sirtuin catalytic core structure. The crystal structure of human SIRT3 in complex with substrate peptide (magenta) and non-hydrolysable NAD⁺ analog (gray; PDB ID 4FVT) illustrates the substrate binding sites. (b) Mechanism of Sirtuin-catalyzed NAD⁺-dependent protein Lys deacylation. (c) Crystal structure of human SIRT1 in complex with FdL substrate peptide (cyan) and three molecules of the STAC resveratrol (green; PDB ID 5BTR). The SIRT1-specific N-terminal STAC binding domain (SBD) and C-terminal regulatory (CTR) segment are indicated. (d) Crystal structure of human SIRT5 in complex with FdL substrate peptide (blue) and the STAC resveratrol (gray; PDB ID 4HDA). (e) Crystal structures of SIRT1 complexes with three different synthetic STACS (green [PDB ID 4ZZH], magenta [PDB ID 4ZZI], orange [PDB ID 4ZZJ]), illustrating that the linker to the SBD allows varying relative orientations of the two domains. Acetyl-peptide and non-hydrolysable NAD⁺ analog (orange) respective a competitive ELT inhibitor (magenta) are also bound and indicate substrate binding sites. (f) Model for transition of the apo SIRT1 open conformation (left) to the “closed” conformation of SIRT1 (right), with the STAC-bound SBD placed on top of the substrate-bound catalytic core. The important electrostatic interaction between Arg446 and Glu230 is indicated. (g) Crystal structure of human SIRT6 in complex with the NAD⁺ fragment ADP-ribose (gray) and the STAC UBCS039 (blue; PDB ID 5MF6).

Figure 3. Sirtuin inhibition

(a) Crystal structure of a SIRT5 complex with inhibitory 3-phenyl-succinyl-modified CPS1 peptide (gray; PDB ID 4UTV), which is closely related to the highly potent and SIRT5 selective 3-phenyl-3-methyl-succinyl-CPS1. Two ligands indicate the two enantiomers. The two key residues recognizing the distal carboxylate are indicated. (b) Crystal structure of SIRT2 in complex with a potent and selective thienopyrimidinone-based inhibitor (PDB ID 5MAT), which exploits the extended acyl channel. (c) Crystal structure of SIRT3 in complex with the product 2′-O-acetyl-ADP-ribose (gray) and the ECS inhibitor Ex-527 (blue; PDB ID 4BVH). The NAM accommodating C-site is indicated by a dotted circle. (d) Crystal structure of SIRT3 in complex with the highly potent pan Sirtuin inhibitor ELT-11c (PDB ID 4JSR), which blocks C site (center; dotted circle) and the channel accommodating the substrate Lys side chain (left part of the inhibitor).