The Pan-ErbB tyrosine kinase inhibitor afatinib inhibits multiple steps of the mammarenavirus life cycle

• Published in: Virology Vol. 576; pp. 83 - 95
• Main Authors: Mizuma, Keita, Takashima, Ayako, Cubitt, Beatrice, de la Torre, Juan C., Iwasaki, Masaharu
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.11.2022; Elsevier BV
• Subjects: Afatinib; Animals; Antiviral; Antiviral Agents; antiviral properties; Arenaviridae; Arenavirus; cell lines; Chlorocebus aethiops; ErbB; Food and Drug Administration; gene expression; Humans; Infectious Disease; Junín virus; Lassa Fever; Lassa mammarenavirus; Lassa virus; Lassa virus fever; LCMV; Life Cycle Stages; Lymphocytic choriomeningitis mammarenavirus; Lymphocytic choriomeningitis virus; pathogens; Protein Kinase Inhibitors; Replication; reporter genes; Ribonucleoproteins; Transcription; tyrosine; Vaccines; Vero Cells; virology; viruses; Junín virus; LCMV; Afatinib; Transcription; Replication; Antiviral; Lassa virus; ErbB; Arenavirus
• ISSN: 0042-6822; 1096-0341; 1096-0341
• DOI: 10.1016/j.virol.2022.09.005

The mammarenavirus Lassa virus (LASV) causes a life-threatening acute febrile disease, Lassa fever (LF). To date, no US Food and Drug Administration (FDA)-licensed medical countermeasures against LASV are available. This underscores the need for the development of novel anti-LASV drugs. Here, we screen an FDA-approved drug library to identify novel anti-LASV drug candidates using an infectious-free cell line expressing a functional LASV ribonucleoprotein (vRNP), where levels of vRNP-directed reporter gene expression serve as a surrogate for vRNP activity. Our screen identified the pan-ErbB tyrosine kinase inhibitor afatinib as a potent inhibitor of LASV vRNP activity. Afatinib inhibited multiplication of lymphocytic choriomeningitis virus (LCMV) a mammarenavirus closely related to LASV. Cell-based assays revealed that afatinib inhibited multiple steps of the LASV and LCMV life cycles. Afatinib also inhibited multiplication of Junín virus vaccine strain Candid#1, indicating that afatinib can have antiviral activity against a broad range of human pathogenic mammarenaviruses. •LASV RNP-expressing cell-based screening against a US FDA-approved drug library.•Pan-ErbB tyrosine kinase inhibitor afatinib is a potent inhibitor of LASV RNP.•Afatinib inhibits multiplication of LCMV and Junín virus (JUNV).•Afatinib inhibits multiple steps of the life cycles of LASV, LCMV, and JUNV.