2. Academic Validation
  3. Novel antiviral activity of PAD inhibitors against human beta-coronaviruses HCoV-OC43 and SARS-CoV-2

Novel antiviral activity of PAD inhibitors against human beta-coronaviruses HCoV-OC43 and SARS-CoV-2

  • Antiviral Res. 2022 Apr:200:105278. doi: 10.1016/j.antiviral.2022.105278.
Selina Pasquero 1,  Francesca Gugliesi 1,  Gloria Griffante 2,  Valentina Dell'Oste 1,  Matteo Biolatti 1,  Camilla Albano 1,  Greta Bajetto 3,  Serena Delbue 4,  Lucia Signorini 4,  Maria Dolci 4,  Santo Landolfo 1,  Marco De Andrea 5
Affiliations

Affiliations

  • 1 Department of Public Health and Pediatric Sciences, University of Turin - Medical School, Turin, Italy.
  • 2 Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
  • 3 Department of Public Health and Pediatric Sciences, University of Turin - Medical School, Turin, Italy; CAAD Center for Translational Research on Autoimmune and Allergic Disease, University of Piemonte Orientale, Novara Medical School, Italy.
  • 4 Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, Italy.
  • 5 Department of Public Health and Pediatric Sciences, University of Turin - Medical School, Turin, Italy; CAAD Center for Translational Research on Autoimmune and Allergic Disease, University of Piemonte Orientale, Novara Medical School, Italy. Electronic address: [email protected].
PMID: 35288208 DOI: 10.1016/j.antiviral.2022.105278
Abstract

The current SARS-CoV-2 pandemic, along with the likelihood that new coronavirus strains will appear in the nearby future, highlights the urgent need to develop new effective Antiviral agents. In this scenario, emerging host-targeting antivirals (HTAs), which act on host-cell factors essential for viral replication, are a promising class of Antiviral compounds. Here we show that a new class of HTAs targeting peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes catalyzing protein citrullination, is endowed with a potent inhibitory activity against human beta-coronaviruses (HCoVs). Specifically, we show that Infection of human fetal lung fibroblasts with HCoV-OC43 leads to enhanced protein citrullination through transcriptional activation of PAD4, and that inhibition of PAD4-mediated citrullination with either of the two pan-PAD inhibitors Cl-A and BB-Cl or the PAD4-specific inhibitor GSK199 curbs HCoV-OC43 replication. Furthermore, we show that either Cl-A or BB-Cl treatment of African green monkey kidney Vero-E6 cells, a widely used cell system to study beta-CoV replication, potently suppresses HCoV-OC43 and SARS-CoV-2 replication. Overall, our results demonstrate the potential efficacy of PAD inhibitors, in suppressing HCoV Infection, which may provide the rationale for the repurposing of this class of inhibitors for the treatment of COVID-19 patients.

Keywords

Citrullination; Coronavirus; HCoV-OC43; Host-targeting antivirals; Peptidyl-arginine deiminases; SARS-CoV-2.

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