| Structural highlights
Function
SIR2_HUMAN NAD-dependent protein deacetylase, which deacetylates internal lysines on histone and non-histone proteins. Deacetylates 'Lys-40' of alpha-tubulin. Involved in the control of mitotic exit in the cell cycle, probably via its role in the regulation of cytoskeleton. Deacetylates PCK1, opposing proteasomal degradation. Deacetylates 'Lys-310' of RELA.[1] [2] [3] [4]
Publication Abstract from PubMed
Sirtuins (SIRTs) are nicotinamide adenine dinucleotide (NAD(+))-dependent lysine deacylases linked to key physiological and disease processes. Here, we report a new class of mechanism-based 1,2,3-triazole inhibitors that hijack SIRT catalysis by forming stalled triazolium- or triazole-ADP-ribose (ADPR) adducts derived from the cofactor NAD(+). These trapped adducts inhibit the enzyme without covalent protein modification, prompting us to term the compounds "Sirtuin Trapping Ligands" (SirTraps). X-ray crystallography and kinetics, together with mass spectrometry confirming adduct formation both in vitro and in cellulo, reveal that the triazole N3 of peptide- and small-molecule-based SirTraps triggers nucleophilic attack at C1' of the nicotinamide riboside moiety of NAD(+), mimicking the first deacylation step. Adduct formation critically depends on precise triazole positioning within the acyl-lysine channel and can be tuned through scaffold design, enabling potent and isoform-selective inhibition. Unlike thiocarbonyl-based NAD(+)-targeting SIRT inhibitors, which may suffer from instability and off-target effects, SirTraps combine high stability, synthetic accessibility, and structural tunability, while demonstrating nanomolar cellular target engagement confirmed by NanoBRET assays. Beyond SIRTs, this inhibition strategy may extend to other NAD(+)-dependent enzymes, including ADP-ribosyltransferases, opening new avenues for mechanism-driven drug discovery.
From Pharmacophore to Warhead: NAD(+)-Targeting Triazoles as Mechanism-Based Sirtuin Inhibitors.,Friedrich F, Meleshin M, Papenkordt N, Gaitzsch L, Prucker I, Borso M, Ruprecht J, Vorreiter C, Rast S, Zhang L, Schiedel M, Sippl W, Imhof A, Jessen HJ, Einsle O, Schutkowski M, Jung M Angew Chem Int Ed Engl. 2025 Oct 30:e16782. doi: 10.1002/anie.202516782. PMID:41165483[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ North BJ, Marshall BL, Borra MT, Denu JM, Verdin E. The human Sir2 ortholog, SIRT2, is an NAD+-dependent tubulin deacetylase. Mol Cell. 2003 Feb;11(2):437-44. PMID:12620231
- ↑ Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA. Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol Cell Biol. 2003 May;23(9):3173-85. PMID:12697818
- ↑ Rothgiesser KM, Erener S, Waibel S, Luscher B, Hottiger MO. SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310. J Cell Sci. 2010 Dec 15;123(Pt 24):4251-8. doi: 10.1242/jcs.073783. Epub 2010 Nov, 16. PMID:21081649 doi:10.1242/jcs.073783
- ↑ Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011 Jul 8;43(1):33-44. doi: 10.1016/j.molcel.2011.04.028. PMID:21726808 doi:10.1016/j.molcel.2011.04.028
- ↑ Friedrich F, Meleshin M, Papenkordt N, Gaitzsch L, Prucker I, Borso M, Ruprecht J, Vorreiter C, Rast S, Zhang L, Schiedel M, Sippl W, Imhof A, Jessen HJ, Einsle O, Schutkowski M, Jung M. From Pharmacophore to Warhead: NAD(+)-Targeting Triazoles as Mechanism-Based Sirtuin Inhibitors. Angew Chem Int Ed Engl. 2025 Oct 30:e16782. PMID:41165483 doi:10.1002/anie.202516782
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