The complex structure of GRL0617 and SARS-CoV-2 PLpro reveals a hot spot for antiviral drug discovery

  • Nat Commun. 2021 Jan 20;12(1):488. doi: 10.1038/s41467-020-20718-8.
Ziyang Fu   #  1  2 ,  Bin Huang   #  1  2 ,  Jinle Tang   #  1  2 ,  Shuyan Liu   #  3 ,  Ming Liu  1  2 ,  Yuxin Ye  1  2 ,  Zhihong Liu  1  2 ,  Yuxian Xiong  1  2 ,  Wenning Zhu  1  2 ,  Dan Cao  1  2 ,  Jihui Li  1  2 ,  Xiaogang Niu  4 ,  Huan Zhou  5 ,  Yong Juan Zhao  1 ,  Guoliang Zhang  6 ,  Hao Huang  7  8
Affiliations
  • 1. State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • 2. Laboratory of Structural Biology and Drug Discovery, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
  • 3. National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China.
  • 4. College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing, 100871, China.
  • 5. Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, China.
  • 6. National Clinical Research Center for Infectious Diseases, Shenzhen Third People's Hospital, Southern University of Science and Technology, Shenzhen, 518112, China. [email protected].
  • 7. State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. [email protected].
  • 8. Laboratory of Structural Biology and Drug Discovery, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. [email protected].
  • # Contributed equally.
PMID: 33473130 DOI: 10.1038/s41467-020-20718-8
Abstract

SARS-CoV-2 is the pathogen responsible for the COVID-19 pandemic. The SARS-CoV-2 papain-like cysteine protease (PLpro) has been implicated in playing important roles in virus maturation, dysregulation of host inflammation, and Antiviral immune responses. The multiple functions of PLpro render it a promising drug target. Therefore, we screened a library of approved drugs and also examined available inhibitors against PLpro. Inhibitor GRL0617 showed a promising in vitro IC50 of 2.1 μM and an effective Antiviral inhibition in cell-based assays. The co-crystal structure of SARS-CoV-2 PlproC111S in complex with GRL0617 indicates that GRL0617 is a non-covalent inhibitor and it resides in the ubiquitin-specific proteases (USP) domain of PLpro. NMR data indicate that GRL0617 blocks the binding of ISG15 C-terminus to PLpro. Using truncated ISG15 mutants, we show that the C-terminus of ISG15 plays a dominant role in binding PLpro. Structural analysis reveals that the ISG15 C-terminus binding pocket in PLpro contributes a disproportionately large portion of binding energy, thus this pocket is a hot spot for Antiviral drug discovery targeting PLpro.

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