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@ARTICLE{Srinivasan:480474,
      author       = {Srinivasan, Vasundara and Brognaro, Hévila and Prabhu,
                      Prince R. and de Souza, Edmarcia Elisa and Günther,
                      Sebastian and Reinke, Patrick Y. A. and Lane, Thomas J. and
                      Ginn, Helen and Han, Huijong and Ewert, Wiebke and Sprenger,
                      Janina and Koua, Faisal H. M. and Falke, Sven and Werner,
                      Nadine and Andaleeb, Hina and Ullah, Najeeb and Franca,
                      Bruno Alves and Wang, Mengying and Barra, Angélica Luana C
                      and Perbandt, Markus and Schwinzer, Martin and Schmidt,
                      Christina and Brings, Lea and Lorenzen, Kristina and
                      Schubert, Robin and Guaragna Machado, Rafael Rahal and
                      Candido, Erika Donizette and Leal Oliveira, Danielle Bruna
                      and Durigon, Edison Luiz and Yefanov, Oleksandr and Lieske,
                      Julia and Gelisio, Luca and Domaracky, Martin and
                      Middendorf, Philipp and Groessler, Michael and Trost, Fabian
                      and Galchenkova, Marina and Saouane, Sofiane and Hakanpää,
                      Johanna and Wolf, Markus and Turk, Dusan and Pearson, Arwen
                      R. and Chapman, Henry N. and Hinrichs, Winfried and Wrenger,
                      Carsten and Meents, Alke and Betzel, Christian},
      title        = {{SARS}-{C}o{V}-2 papain-like protease {PL}pro in complex
                      with natural compounds reveal allosteric sites for antiviral
                      drug design},
      reportid     = {PUBDB-2022-03779},
      year         = {2021},
      abstract     = {SARS-CoV-2 papain-like protease (PLpro) covers multiple
                      functions. Beside the cysteine-protease activity, PLpro has
                      the additional and vital function of removing ubiquitin and
                      ISG15 (Interferon-stimulated gene 15) from host-cell
                      proteins to aid coronaviruses in evading the host’s innate
                      immune responses. We established a high-throughput X-ray
                      screening to identify inhibitors by elucidating the native
                      PLpro structure refined to 1.42 Å and performing
                      co-crystallization utilizing a diverse library of selected
                      natural compounds. We identified three phenolic compounds as
                      potential inhibitors. Crystal structures of PLpro inhibitor
                      complexes, obtained to resolutions between 1.7-1.9 Å, show
                      that all three compounds bind at the ISG15/Ub-S2 allosteric
                      binding site, preventing the essential ISG15-PLpro molecular
                      interactions. All compounds demonstrate clear inhibition in
                      a deISGylation assay, two exhibit distinct antiviral
                      activity and one inhibited a cytopathic effect in a
                      non-cytotoxic concentration range. These results highlight
                      the druggability of the rarely explored ISG15/Ub-S2 PLpro
                      allosteric binding site to identify new and effective
                      antiviral compounds. Importantly, in the context of
                      increasing PLpro mutations in the evolving new variants of
                      SARS-CoV-2, the natural compounds we identified may also
                      reinstate the antiviral immune response processes of the
                      host that are down-regulated in COVID-19 infections.},
      cin          = {FS-CFEL-1-BMX / DOOR ; HAS-User / EMBL / FS-CFEL-1-PBIO /
                      CFEL-I / FS-PET-D / CFEL-TRSB},
      cid          = {I:(DE-H253)FS-CFEL-1-BMX-20210408 /
                      I:(DE-H253)HAS-User-20120731 / I:(DE-H253)EMBL-20120731 /
                      I:(DE-H253)FS-CFEL-1-PBIO-20210408 /
                      I:(DE-H253)CFEL-I-20161114 / I:(DE-H253)FS-PET-D-20190712 /
                      I:(DE-H253)CFEL-TRSB-20161025},
      pnm          = {633 - Life Sciences – Building Blocks of Life: Structure
                      and Function (POF4-633) / 6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-633 / G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P11-20150101},
      typ          = {PUB:(DE-HGF)25},
      doi          = {10.1101/2021.11.17.468943},
      url          = {https://bib-pubdb1.desy.de/record/480474},
}