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

• Published in: Cell chemical biology Vol. 29; no. 5; pp. 774 - 784.e8
• Main Authors: Napolitano, Valeria, Dabrowska, Agnieszka, Schorpp, Kenji, Mourão, André, Barreto-Duran, Emilia, Benedyk, Malgorzata, Botwina, Pawel, Brandner, Stefanie, Bostock, Mark, Chykunova, Yuliya, Czarna, Anna, Dubin, Grzegorz, Fröhlich, Tony, Hölscher, Michael, Jedrysik, Malwina, Matsuda, Alex, Owczarek, Katarzyna, Pachota, Magdalena, Plettenburg, Oliver, Potempa, Jan, Rothenaigner, Ina, Schlauderer, Florian, Slysz, Klaudia, Szczepanski, Artur, Greve-Isdahl Mohn, Kristin, Blomberg, Bjorn, Sattler, Michael, Hadian, Kamyar, Popowicz, Grzegorz Maria, Pyrc, Krzysztof
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 19.05.2022; The Authors. Published by Elsevier Ltd
• Subjects: acriflavine; coronavirus; COVID-19; drug repurposing; PLpro; protease; protease inhibitor; SARS-CoV-2; structural biology; COVID-19; protease; SARS-CoV-2; protease inhibitor; drug repurposing; acriflavine; coronavirus; PLpro; structural biology; PL(pro)
• ISSN: 2451-9456; 2451-9456; 2451-9448
• DOI: 10.1016/j.chembiol.2021.11.006

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. [Display omitted] •Acriflavine (ACF) is a potent inhibitor of SARS-CoV-2 papain-like protease PLpro•A co-crystal structure shows how ACF blocks the active site with a unique binding mode•ACF has low-nanomolar IC50in vitro, ex vivo, and in animal models•ACF is a registered drug and a promising candidate for clinical studies Napolitano et al. discovered acriflavine (ACF), a clinically approved drug, as an effective inhibitor of SARS-CoV-2 papain-like protease (PLpro). ACF inhibits viral replication at nanomolar concentrations in vitro and ex vivo, as well as in vivo. These findings open a promising therapeutic approach against COVID-19 and other betacoronaviruses.