Drug repurposing screen identifies masitinib as a 3CLpro inhibitor that blocks replication of SARS-CoV-2 in vitro

Nir Drayman, Krysten A. Jones, Saara-Anne Azizi, Heather M. Froggatt, Kemin Tan, Natalia Ivanovna Maltseva, Siquan Chen, Vlad Nicolaescu, Steve Dvorkin, Kevin Furlong, Rahul S. Kathayat, Mason R. Firpo, Vincent Mastrodomenico, Emily A. Bruce, Madaline M. Schmidt, Robert Jedrzejczak, Miguel Á. Muñoz-Alía, Brooke Schuster, Vishnu Nair, Jason W. Botten, Christopher B. Brooke, Susan C. Baker, Bryan C. Mounce, Nicholas S. Heaton, Bryan C. Dickinson, Andrzej Jaochimiak, Glenn Randall, Savaş Tay

10.1101/2020.08.31.274639

Research curated

Abstract

There is an urgent need for anti-viral agents that treat SARS-CoV-2 infection. The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first screened a library of 1,900 clinically safe drugs for inhibiting replication of OC43, a human beta-coronavirus that causes the common-cold and is a relative of SARS-CoV-2, and identified 108 effective drugs. We further evaluated the top 26 hits and determined their ability to inhibit SARS-CoV-2, as well as other pathogenic RNA viruses. 20 of the 26 drugs significantly inhibited SARS-CoV-2 replication in human lung cells (A549 epithelial cell line), with EC50 values ranging from 0.1 to 8 micromolar. We investigated the mechanism of action for these and found that masitinib, a drug originally developed as a tyrosine-kinase inhibitor for cancer treatment, strongly inhibited the activity of the SARS-CoV-2 main protease 3CLpro. X-ray crystallography revealed that masitinib directly binds to the active site of 3CLpro, thereby blocking its enzymatic activity. Mastinib also inhibited the related viral protease of picornaviruses and blocked picornaviruses replication. Thus, our results show that masitinib has broad anti-viral activity against two distinct beta-coronaviruses and multiple picornaviruses that cause human disease and is a strong candidate for clinical trials to treat SARS-CoV-2 infection.

Source: BioRxiv

Related molecules

Name	Synonyms	Genes
Nortriptyline
Propafenone
Desloratadine
Trimipramine
Solifenacin
Clomipramine
Benzatropine
Pentoxyverine
Cediranib
Retapamulin
Conivaptan
Bafetinib
Vilazodone
Masitinib
Azelastine
Lapatinib
3C-like protease	3CLpro, Mpro, SARS coronavirus main peptidase, 3CLpro-SARS-CoV-2	rep, ORF1a-1b
Flupentixol
Raloxifene
Imatinib	Imatinib mesylate, Gleevec
Masitinib
Cepharanthine	CEP

Related interactions

Target	Drug	Type	Result
3C-like protease	Nortriptyline	In vitro	negative
3C-like protease	Propafenone	In vitro	negative
3C-like protease	Azelastine	In vitro	negative
3C-like protease	Desloratadine	In vitro	negative
3C-like protease	Trimipramine	In vitro	negative
3C-like protease	Solifenacin	In vitro	negative
3C-like protease	Clomipramine	In vitro	negative
3C-like protease	Cepharanthine	In vitro	negative
3C-like protease	Benzatropine	In vitro	negative
3C-like protease	Pentoxyverine	In vitro	negative
3C-like protease	Cediranib	In vitro	negative
3C-like protease	Retapamulin	In vitro	positive
3C-like protease	Conivaptan	In vitro	positive
3C-like protease	Bafetinib	In vitro	positive
3C-like protease	Imatinib	In vitro	positive
3C-like protease	Lapatinib	In vitro	positive
3C-like protease	Vilazodone	In vitro	positive
3C-like protease	Masitinib	In vitro	positive
3C-like protease	Flupentixol	In vitro	negative
3C-like protease	Raloxifene	In vitro	positive