Preprint PUBDB-2022-03779

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SARS-CoV-2 papain-like protease PLpro in complex with natural compounds reveal allosteric sites for antiviral drug design

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2021

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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.


Contributing Institute(s):
  1. FS-CFEL-1 Fachgruppe BMX (FS-CFEL-1-BMX)
  2. DOOR-User (DOOR ; HAS-User)
  3. EMBL (EMBL)
  4. FS-CFEL-1 Fachgruppe PBIO (FS-CFEL-1-PBIO)
  5. FS-CFEL-1 (Group Leader: Henry Chapman) (CFEL-I)
  6. Experimentebetreuung PETRA III (FS-PET-D)
  7. Arwen Pearson - CUI (CFEL-TRSB)
Research Program(s):
  1. 633 - Life Sciences – Building Blocks of Life: Structure and Function (POF4-633) (POF4-633)
  2. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
Experiment(s):
  1. PETRA Beamline P11 (PETRA III)

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Private Collections > >CFEL > >FS-CFEL > FS-CFEL-1-PBIO
Private Collections > >CFEL > >FS-CFEL > FS-CFEL-1-BMX
Private Collections > >CFEL > >UNI-CFEL > CFEL-TRSB
Private Collections > >CFEL > >FS-CFEL > CFEL-I
Private Collections > >Extern > >HAS-User > HAS-User
Private Collections > >DESY > >FS > FS-PET-D
Private Collections > >EMBL > EMBL
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 Record created 2022-07-12, last modified 2022-10-19


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