Open AccessScreening of Botanical Drugs against Lassa Virus Entry
Author(s) -
Yang Liu,
Jiao Guo,
Jiashu Cao,
Guangshun Zhang,
Xiaoying Jia,
Peilin Wang,
Gengfu Xiao,
Wei Wang
Publication year - 2021
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.02429-20
Subject(s) - lassa virus , arenavirus , virology , lassa fever , biology , viral entry , lipid bilayer fusion , entry inhibitor , lymphocytic choriomeningitis , virus , viral replication , immunology , antigen , cd8
Lassa virus (LASV) belongs to the Old World Mammarenavirus genus (family Arenaviridae ). At present, there are no approved drugs or vaccines specific for LASV. In this study, high-throughput screening of a botanical drug library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two hit compounds, bergamottin and casticin, were identified as micromolar range inhibitors of LASV entry. A mechanistic study revealed that casticin inhibited LASV entry by blocking low pH-induced membrane fusion. Analysis of adaptive mutants demonstrated that the F446L mutation, located in the transmembrane domain of GP2, conferred resistance to casticin. Furthermore, casticin antiviral activity extends to the New World (NW) pathogenic mammarenaviruses, and mutation of the conserved F446 also conferred resistance to casticin in these viruses. Unlike casticin, bergamottin showed little effect on LASV GPC-mediated membrane fusion, instead inhibiting LASV entry by blocking endocytic trafficking. Notably, both compounds showed inhibitory effects on authentic lymphocytic choriomeningitis virus. Our study shows that both casticin and bergamottin are candidates for LASV therapy and that the conserved F446 in LASV GPC is important in drug resistance in mammarenaviruses. IMPORTANCE: Currently, there is no approved therapy to treat Lassa fever (LASF). Our goal was to identify potential candidate molecules for LASF therapy. Herein, we screened a botanical drug library and identified two compounds, casticin and bergamottin, that inhibited LASV entry via different mechanisms.