Deubiquitinating enzymes in coronaviruses and possible therapeutic opportunities for COVID-19

Valentino Clemente, Padraig D’arcy, Martina Bazzaro

Research output: Contribution to journalReview articlepeer-review

5 Scopus citations


Following the outbreak of novel severe acute respiratory syndrome (SARS)-coronavirus (CoV)2, the majority of nations are struggling with countermeasures to fight infection, prevent spread and improve patient survival. Considering that the pandemic is a recent event, no large clinical trials have been possible and since coronavirus specific drug are not yet available, there is no strong consensus on how to treat the coronavirus disease 2019 (COVID-19) associated viral pneumonia. Coronaviruses code for an important multifunctional enzyme named papain-like protease (PLP), that has many roles in pathogenesis. First, PLP is one of the two viral cysteine proteases, along with 3-chymotripsin-like protease, that is responsible for the production of the replicase proteins required for viral replication. Second, its intrinsic deubiquitinating and deISGylating activities serve to antagonize the host’s immune response that would otherwise hinder infection. Both deubiquitinating and deISGylating functions involve the removal of the small regulatory polypeptides, ubiquitin and ISG15, respectively, from target proteins. Ubiquitin modifications can regulate the innate immune response by affecting regulatory proteins, either by altering their stability via the ubiquitin proteasome pathway or by directly regulating their activity. ISG15 is a ubiquitin-like modifier with pleiotropic effects, typically expressed during the host cell immune response. PLP inhibitors have been evaluated during past coronavirus epidemics, and have showed promising results as an antiviral therapy in vitro. In this review, we recapitulate the roles of PLPs in coronavirus infections, report a list of PLP inhibitors and suggest possible therapeutic strategies for COVID-19 treatment, using both clinical and preclinical drugs.

Original languageEnglish (US)
Article number3492
JournalInternational journal of molecular sciences
Issue number10
StatePublished - May 2 2020

Bibliographical note

Funding Information:
Funding: This work was supported by the Department of Defense Ovarian Cancer Research Program Grant OC160377, the Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research Funds and the NIH grant 1R01GM130800-01A1 to Martina Bazzaro. This work was supported by the Swedish Research Council to Padraig D’Arcy. This work was supported by Rotary Club Forlì to Valentino Clemente. The funders had no role in the decision to publish or prepare the manuscript. The authors declare no conflict of interests.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.


  • COVID-19
  • COVID-19 therapy
  • Coronavirus
  • DUBs
  • PLP inhibitors
  • Papain-like protease
  • SARS
  • SARS-CoV2

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