Lassa virus (LASV) belongs to the Old World Mammarenavirus genus (family Arenaviridae) and is classified as a category A biological threat agent. 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 (GPC). Two hit compounds, bergamottin and casticin, were identified as LASV entry inhibitors in the micromolar range. A mechanistic study revealed that casticin inhibited LASV entry by blocking low pH-induced membrane fusion. Adaptive mutant analyses demonstrated that the F446L mutation, located in the transmembrane domain of GP2, conferred resistance to casticin. Furthermore, casticin extended its antiviral spectrum to the New World (NW) pathogenic mammarenaviruses, and mutation of the conserved F446 conferred NW resistance to casticin. Unlike casticin, bergamottin has little effect on LASV GPC-mediated membrane fusion, while it inhibited LASV entry by blocking endocytic trafficking. Our study shows that both bergamottin and casticin are candidates for LASV therapy, indicating that the conserved F446 plays important roles in drug resistance in mammarenaviruses.

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