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

Research output: Contribution to journalArticleResearchpeer review

Authors

  • Valeria Napolitano
  • Agnieszka Dabrowska
  • Kenji Schorpp
  • André Mourão
  • Emilia Barreto-Duran
  • Malgorzata Benedyk
  • Pawel Botwina
  • Stefanie Brandner
  • Mark Bostock
  • Yuliya Chykunova
  • Anna Czarna
  • Grzegorz Dubin
  • Tony Fröhlich
  • Michael Hölscher
  • Malwina Jedrysik
  • Alex Matsuda
  • Katarzyna Owczarek
  • Magdalena Pachota
  • Oliver Plettenburg
  • Jan Potempa
  • Ina Rothenaigner
  • Florian Schlauderer
  • Klaudia Slysz
  • Artur Szczepanski
  • Kristin Greve-Isdahl Mohn
  • Bjorn Blomberg
  • Michael Sattler
  • Kamyar Hadian
  • Grzegorz Maria Popowicz
  • Krzysztof Pyrc

External Research Organisations

  • Helmholtz Zentrum München - German Research Center for Environmental Health
  • Jagiellonian University
  • Ludwig-Maximilians-Universität München (LMU)
  • Justus Liebig University Giessen
  • Technical University of Munich (TUM)
  • Haukeland University Hospital
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Details

Original languageEnglish
Pages (from-to)774-784
JournalCell Chemical Biology
Volume29
Issue number5
Early online date11 Jan 2022
Publication statusPublished - 19 May 2022

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

    acriflavine, coronavirus, COVID-19, drug repurposing, PL, protease, protease inhibitor, SARS-CoV-2, structural biology

ASJC Scopus subject areas

Sustainable Development Goals

Cite this

Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses. / Napolitano, Valeria; Dabrowska, Agnieszka; Schorpp, Kenji et al.
In: Cell Chemical Biology, Vol. 29, No. 5, 19.05.2022, p. 774-784.

Research output: Contribution to journalArticleResearchpeer review

Napolitano, V, Dabrowska, A, Schorpp, K, Mourão, A, Barreto-Duran, E, Benedyk, M, Botwina, P, Brandner, S, Bostock, M, Chykunova, Y, Czarna, A, Dubin, G, Fröhlich, T, Hölscher, M, Jedrysik, M, Matsuda, A, Owczarek, K, Pachota, M, Plettenburg, O, Potempa, J, Rothenaigner, I, Schlauderer, F, Slysz, K, Szczepanski, A, Greve-Isdahl Mohn, K, Blomberg, B, Sattler, M, Hadian, K, Popowicz, GM & Pyrc, K 2022, 'Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses', Cell Chemical Biology, vol. 29, no. 5, pp. 774-784. https://doi.org/10.1016/j.chembiol.2021.11.006
Napolitano, V., Dabrowska, A., Schorpp, K., Mourão, A., Barreto-Duran, E., Benedyk, M., Botwina, P., Brandner, S., Bostock, M., Chykunova, Y., Czarna, A., Dubin, G., Fröhlich, T., Hölscher, M., Jedrysik, M., Matsuda, A., Owczarek, K., Pachota, M., Plettenburg, O., ... Pyrc, K. (2022). Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses. Cell Chemical Biology, 29(5), 774-784. https://doi.org/10.1016/j.chembiol.2021.11.006
Napolitano V, Dabrowska A, Schorpp K, Mourão A, Barreto-Duran E, Benedyk M et al. Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses. Cell Chemical Biology. 2022 May 19;29(5):774-784. Epub 2022 Jan 11. doi: 10.1016/j.chembiol.2021.11.006
Napolitano, Valeria ; Dabrowska, Agnieszka ; Schorpp, Kenji et al. / Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses. In: Cell Chemical Biology. 2022 ; Vol. 29, No. 5. pp. 774-784.
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title = "Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses",
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.",
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note = "Funding Information: This work was supported by a subsidy from the Polish Ministry of Science and Higher Education for research on SARS-CoV-2 and a grant from the National Science Center (UMO-2017/27/B/NZ6/02488) and by EU-Horizon2020 ITN OrganoVir grant 812673 (to K.P). Support by the Bayerische Forschungsstiftung grant AZ-1453-20C (to M.S. and G.P.) is acknowledged. K.O. was supported by the Foundation for Polish Science. Conceptualization, M.S. K.H. G.P. and K.P.; methodology, formal analysis, and investigation, V.N. K.S. F.S. A.M. A.D. E.B.D. M.B. P.B. Y.C. A.C. G.D. K.O. M.P. J.P. A.S. K.G.I.M. B.B. G.P. and K.P.; writing – original draft, K.P. G.P. K.H. and M.S.; writing – review & editing, all authors; funding acquisition and supervision, M.S. K.H. G.P. and K.P. ACF and its derivatives and their use against betacoronaviruses are protected by European patent application no. 20214108.1, submitted by the authors of this paper. Disclosure statement: M.J.B. is a current employee of AstraZeneca. ",
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T1 - Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses

AU - Napolitano, Valeria

AU - Dabrowska, Agnieszka

AU - Schorpp, Kenji

AU - Mourão, André

AU - Barreto-Duran, Emilia

AU - Benedyk, Malgorzata

AU - Botwina, Pawel

AU - Brandner, Stefanie

AU - Bostock, Mark

AU - Chykunova, Yuliya

AU - Czarna, Anna

AU - Dubin, Grzegorz

AU - Fröhlich, Tony

AU - Hölscher, Michael

AU - Jedrysik, Malwina

AU - Matsuda, Alex

AU - Owczarek, Katarzyna

AU - Pachota, Magdalena

AU - Plettenburg, Oliver

AU - Potempa, Jan

AU - Rothenaigner, Ina

AU - Schlauderer, Florian

AU - Slysz, Klaudia

AU - Szczepanski, Artur

AU - Greve-Isdahl Mohn, Kristin

AU - Blomberg, Bjorn

AU - Sattler, Michael

AU - Hadian, Kamyar

AU - Popowicz, Grzegorz Maria

AU - Pyrc, Krzysztof

N1 - Funding Information: This work was supported by a subsidy from the Polish Ministry of Science and Higher Education for research on SARS-CoV-2 and a grant from the National Science Center (UMO-2017/27/B/NZ6/02488) and by EU-Horizon2020 ITN OrganoVir grant 812673 (to K.P). Support by the Bayerische Forschungsstiftung grant AZ-1453-20C (to M.S. and G.P.) is acknowledged. K.O. was supported by the Foundation for Polish Science. Conceptualization, M.S. K.H. G.P. and K.P.; methodology, formal analysis, and investigation, V.N. K.S. F.S. A.M. A.D. E.B.D. M.B. P.B. Y.C. A.C. G.D. K.O. M.P. J.P. A.S. K.G.I.M. B.B. G.P. and K.P.; writing – original draft, K.P. G.P. K.H. and M.S.; writing – review & editing, all authors; funding acquisition and supervision, M.S. K.H. G.P. and K.P. ACF and its derivatives and their use against betacoronaviruses are protected by European patent application no. 20214108.1, submitted by the authors of this paper. Disclosure statement: M.J.B. is a current employee of AstraZeneca.

PY - 2022/5/19

Y1 - 2022/5/19

N2 - 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.

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KW - coronavirus

KW - COVID-19

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KW - protease

KW - protease inhibitor

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