2. Academic Validation
  3. Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses

Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses

  • Cell Chem Biol. 2022 May 19;29(5):774-784.e8. doi: 10.1016/j.chembiol.2021.11.006.
Valeria Napolitano 1,  Agnieszka Dabrowska 2,  Kenji Schorpp 1,  André Mourão 1,  Emilia Barreto-Duran 3,  Malgorzata Benedyk 4,  Pawel Botwina 2,  Stefanie Brandner 1,  Mark Bostock 5,  Yuliya Chykunova 2,  Anna Czarna 3,  Grzegorz Dubin 3,  Tony Fröhlich 1,  Michael Hölscher 6,  Malwina Jedrysik 3,  Alex Matsuda 3,  Katarzyna Owczarek 3,  Magdalena Pachota 2,  Oliver Plettenburg 7,  Jan Potempa 4,  Ina Rothenaigner 1,  Florian Schlauderer 1,  Klaudia Slysz 4,  Artur Szczepanski 2,  Kristin Greve-Isdahl Mohn 8,  Bjorn Blomberg 8,  Michael Sattler 9,  Kamyar Hadian 10,  Grzegorz Maria Popowicz 11,  Krzysztof Pyrc 12
Affiliations

Affiliations

  • 1 Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany.
  • 2 Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland; Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
  • 3 Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland.
  • 4 Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland.
  • 5 Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Bavarian NMR Center, Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85748 Garching, Germany.
  • 6 Division of Infectious Diseases and Tropical Medicine, University Hospital, LMU Munich, Leopoldstrasse 5, 80802 Munich, Germany.
  • 7 Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Centre of Biomolecular Drug Research (BMWZ), Institute of Organic Chemistry, Leibniz Universität Hannover, Hannover, Germany; Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.
  • 8 Haukeland University Hospital, Bergen, Norway.
  • 9 Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Bavarian NMR Center, Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85748 Garching, Germany. Electronic address: sattler@helmholtz-muenchen.de.
  • 10 Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany. Electronic address: kamyar.hadian@helmholtz-muenchen.de.
  • 11 Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764 Neuherberg, Germany; Bavarian NMR Center, Department of Chemistry, Technical University of Munich, Lichtenbergstrasse 4, 85748 Garching, Germany. Electronic address: grzegorz.popowicz@helmholtz-muenchen.de.
  • 12 Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland. Electronic address: k.a.pyrc@uj.edu.pl.
PMID: 35021060 DOI: 10.1016/j.chembiol.2021.11.006
Abstract

The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort and available vaccines, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identify acriflavine (ACF) as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and Other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

Keywords

COVID-19; PL(pro); SARS-CoV-2; acriflavine; coronavirus; drug repurposing; protease; protease inhibitor; structural biology.

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