% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Friedrich:305586,
      author       = {F. Friedrich and M. Meleshin and N. Papenkordt and L.
                      Gaitzsch and I. Prucker and M. Borso and J. Ruprecht and C.
                      Vorreiter and S. Rast$^*$ and L. Zhang and M. Schiedel and
                      W. Sippl and A. Imhof and H. J. Jessen and O. Einsle and M.
                      Schutkowski and M. Jung$^*$},
      title        = {{F}rom {P}harmacophore to {W}arhead: {NAD}+-{T}argeting
                      {T}riazoles as {M}echanism-{B}ased {S}irtuin {I}nhibitors.},
      journal      = {Angewandte Chemie / International edition},
      volume       = {nn},
      issn         = {1433-7851},
      address      = {Weinheim},
      publisher    = {Wiley-VCH},
      reportid     = {DKFZ-2025-02245},
      pages        = {nn},
      year         = {2025},
      note         = {epub / Communication},
      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.},
      keywords     = {Covalent adduct (Other) / Drug discovery (Other) /
                      Inhibitors (Other) / Sirtuins (Other) / Triazoles (Other)},
      cin          = {FR01},
      ddc          = {540},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41165483},
      doi          = {10.1002/anie.202516782},
      url          = {https://inrepo02.dkfz.de/record/305586},
}