Identification of ebselen and its analogues as potent covalent inhibitors of papain-like protease from SARS-CoV-2

Sci Rep. 2021 Feb 11;11(1):3640. doi: 10.1038/s41598-021-83229-6.


An efficient treatment against a COVID-19 disease, caused by the novel coronavirus SARS-CoV-2 (CoV2), remains a challenge. The papain-like protease (PLpro) from the human coronavirus is a protease that plays a critical role in virus replication. Moreover, CoV2 uses this enzyme to modulate the host's immune system to its own benefit. Therefore, it represents a highly promising target for the development of antiviral drugs. We used Approximate Bayesian Computation tools, molecular modelling and enzyme activity studies to identify highly active inhibitors of the PLpro. We discovered organoselenium compounds, ebselen and its structural analogues, as a novel approach for inhibiting the activity of PLproCoV2. Furthermore, we identified, for the first time, inhibitors of PLproCoV2 showing potency in the nanomolar range. Moreover, we found a difference between PLpro from SARS and CoV2 that can be correlated with the diverse dynamics of their replication, and, putatively to disease progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Azoles / chemistry
  • Azoles / pharmacology*
  • Binding Sites
  • Coronavirus Papain-Like Proteases / antagonists & inhibitors*
  • Coronavirus Papain-Like Proteases / chemistry
  • Coronavirus Papain-Like Proteases / metabolism
  • Isoindoles
  • Molecular Docking Simulation*
  • Organoselenium Compounds / chemistry
  • Organoselenium Compounds / pharmacology*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Protein Binding


  • Antiviral Agents
  • Azoles
  • Isoindoles
  • Organoselenium Compounds
  • Protease Inhibitors
  • ebselen
  • Coronavirus Papain-Like Proteases
  • papain-like protease, SARS-CoV-2