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@ARTICLE{Ewert:475969,
      author       = {Ewert, Wiebke and Günther, Sebastian and Miglioli,
                      Francesca and Falke, Sven and Reinke, Patrick Y. A. and
                      Niebling, Stephan and Guenther, Christian and Han, Huijong
                      and Srinivasan, Vasundara and Brognaro, Hévila and Lieske,
                      Julia and Lorenzen, Kristina and Garcia-Alai, Maria M. and
                      Betzel, Christian and Carcelli, Mauro and Hinrichs, Winfried
                      and Rogolino, Dominga and Meents, Alke},
      title        = {{H}ydrazones and {T}hiosemicarbazones {T}argeting
                      {P}rotein-{P}rotein-{I}nteractions of {SARS}-{C}o{V}-2
                      {P}apain-like {P}rotease},
      journal      = {Frontiers in Chemistry},
      volume       = {10},
      issn         = {2296-2646},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {PUBDB-2022-01546},
      pages        = {832431},
      year         = {2022},
      abstract     = {The papain-like protease (PLpro) of SARS-CoV-2 is essential
                      for viral propagation and, additionally, dysregulation of
                      the host innate immune system. Using a library of 40
                      potential metal-chelating compounds we performed an X-ray
                      crystallographic screening against PLpro. As outcome we
                      identified six compounds binding to the target protein. Here
                      we describe the interaction of one hydrazone (H1) and five
                      thiosemicarbazone (T1-T5) compounds with the two distinct
                      natural substrate binding sites of PLpro for ubiquitin and
                      ISG15. H1 binds to a polar groove at the S1 binding site by
                      forming several hydrogen bonds with PLpro. T1-T5 bind into a
                      deep pocket close to the polyubiquitin and ISG15 binding
                      site S2. Their interactions are mainly mediated by multiple
                      hydrogen bonds and further hydrophobic interactions. In
                      particular compound H1 interferes with natural substrate
                      binding by sterical hindrance and induces conformational
                      changes in protein residues involved in substrate binding,
                      while compounds T1-T5 could have a more indirect effect.
                      Fluorescence based enzyme activity assay and complementary
                      thermal stability analysis reveal only weak inhibition
                      properties in the high micromolar range thereby indicating
                      the need for compound optimization. Nevertheless, the unique
                      binding properties involving strong hydrogen bonding and the
                      various options for structural optimization make the
                      compounds ideal lead structures. In combination with the
                      inexpensive and undemanding synthesis, the reported
                      hydrazone and thiosemicarbazones represent an attractive
                      scaffold for further structure-based development of novel
                      PLpro inhibitors by interrupting protein-protein
                      interactions at the S1 and S2 site.},
      cin          = {FS-CFEL-1-BMX},
      ddc          = {540},
      cid          = {I:(DE-H253)FS-CFEL-1-BMX-20210408},
      pnm          = {633 - Life Sciences – Building Blocks of Life: Structure
                      and Function (POF4-633) / 6G3 - PETRA III (DESY) (POF4-6G3)
                      / FISCOV - FISCOV Helmholtz large research infrastructures
                      in the fight against epidemic outbreaks (FISCOV) / DFG
                      project 390715994 - EXC 2056: CUI: Advanced Imaging of
                      Matter (390715994)},
      pid          = {G:(DE-HGF)POF4-633 / G:(DE-HGF)POF4-6G3 / G:(DE-HGF)FISCOV
                      / G:(GEPRIS)390715994},
      experiment   = {EXP:(DE-H253)P-P11-20150101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {35480391},
      UT           = {WOS:000792403500001},
      doi          = {10.3389/fchem.2022.832431},
      url          = {https://bib-pubdb1.desy.de/record/475969},
}