Journal Article

DKFZ-2025-02245

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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.DKFZ* ; Zhang, L. ; Schiedel, M. ; Sippl, W. ; Imhof, A. ; Jessen, H. J. ; Einsle, O. ; Schutkowski, M. ; Jung, M.DKFZ*

2025
Wiley-VCH Weinheim

Abstract: 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.

Keyword(s): Covalent adduct ; Drug discovery ; Inhibitors ; Sirtuins ; Triazoles

Note: epub

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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Database coverage:
; Chemical Reactions ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; Index Chemicus ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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