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

authored by: 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
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 (PL^pro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PL^pro 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.
Organisation(s): Centre of Biomolecular Drug Research (BMWZ)
Institute of Organic Chemistry
External Organisation(s): 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
Type: Article
Journal: Cell Chemical Biology
Volume: 29
Pages: 774-784
ISSN: 2451-9456
Publication date: 19.05.2022
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: Biochemistry, Molecular Medicine, Molecular Biology, Pharmacology, Drug Discovery, Clinical Biochemistry
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Electronic version(s): https://doi.org/10.1016/j.chembiol.2021.11.006 (Access: Open)

BibTeX

@article{5c74c5d9d28a4e71b65603e72b1d0555,
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.",
keywords = "acriflavine, coronavirus, COVID-19, drug repurposing, PL, protease, protease inhibitor, SARS-CoV-2, structural biology",
author = "Valeria Napolitano and Agnieszka Dabrowska and Kenji Schorpp and Andr{\'e} Mour{\~a}o and Emilia Barreto-Duran and Malgorzata Benedyk and Pawel Botwina and Stefanie Brandner and Mark Bostock and Yuliya Chykunova and Anna Czarna and Grzegorz Dubin and Tony Fr{\"o}hlich and Michael H{\"o}lscher and Malwina Jedrysik and Alex Matsuda and Katarzyna Owczarek and Magdalena Pachota and Oliver Plettenburg and Jan Potempa and Ina Rothenaigner and Florian Schlauderer and Klaudia Slysz and Artur Szczepanski and {Greve-Isdahl Mohn}, Kristin and Bjorn Blomberg and Michael Sattler and Kamyar Hadian and Popowicz, {Grzegorz Maria} and Krzysztof Pyrc",
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. ",
year = "2022",
month = may,
day = "19",
doi = "10.1016/j.chembiol.2021.11.006",
language = "English",
volume = "29",
pages = "774--784",
journal = "Cell Chemical Biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "5",
}