Details
| Original language | English |
|---|---|
| Pages (from-to) | 774-784 |
| Journal | Cell Chemical Biology |
| Volume | 29 |
| Issue number | 5 |
| Early online date | 11 Jan 2022 |
| Publication status | Published - 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
- Biochemistry, Genetics and Molecular Biology(all)
- Biochemistry
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Biology
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
- Biochemistry, Genetics and Molecular Biology(all)
- Clinical Biochemistry
Sustainable Development Goals
Cite this
- Standard
- Harvard
- Apa
- Vancouver
- BibTeX
- RIS
In: Cell Chemical Biology, Vol. 29, No. 5, 19.05.2022, p. 774-784.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
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.
AB - 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.
KW - acriflavine
KW - coronavirus
KW - COVID-19
KW - drug repurposing
KW - PL
KW - protease
KW - protease inhibitor
KW - SARS-CoV-2
KW - structural biology
UR - http://www.scopus.com/inward/record.url?scp=85122625842&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2021.11.006
DO - 10.1016/j.chembiol.2021.11.006
M3 - Article
C2 - 35021060
AN - SCOPUS:85122625842
VL - 29
SP - 774
EP - 784
JO - Cell Chemical Biology
JF - Cell Chemical Biology
SN - 2451-9456
IS - 5
ER -