CP100356 Hydrochloride, a P-Glycoprotein Inhibitor, Inhibits Lassa Virus Entry: Implication of a Candidate Pan-Mammarenavirus Entry Inhibitor

Author:

Takenaga Toru,Zhang Zihan,Muramoto Yukiko,Fehling Sarah Katharina,Hirabayashi Ai,Takamatsu Yuki,Kajikawa Junichi,Miyamoto ShoORCID,Nakano MasahiroORCID,Urata Shuzo,Groseth AllisonORCID,Strecker ThomasORCID,Noda Takeshi

Abstract

Lassa virus (LASV)—a member of the family Arenaviridae—causes Lassa fever in humans and is endemic in West Africa. Currently, no approved drugs are available. We screened 2480 small compounds for their potential antiviral activity using pseudotyped vesicular stomatitis virus harboring the LASV glycoprotein (VSV-LASVGP) and a related prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV). Follow-up studies confirmed that CP100356 hydrochloride (CP100356), a specific P-glycoprotein (P-gp) inhibitor, suppressed VSV-LASVGP, LCMV, and LASV infection with half maximal inhibitory concentrations of 0.52, 0.54, and 0.062 μM, respectively, without significant cytotoxicity. Although CP100356 did not block receptor binding at the cell surface, it inhibited low-pH-dependent membrane fusion mediated by arenavirus glycoproteins. P-gp downregulation did not cause a significant reduction in either VSV-LASVGP or LCMV infection, suggesting that P-gp itself is unlikely to be involved in arenavirus entry. Finally, our data also indicate that CP100356 inhibits the infection by other mammarenaviruses. Thus, our findings suggest that CP100356 can be considered as an effective virus entry inhibitor for LASV and other highly pathogenic mammarenaviruses.

Funder

Japan Agency for Medical Research and Development

Japan Society for the Promotion of Science

Ministry of Education, Culture, Sports, Science and Technology

Japan Science and Technology Agency

Deutsche Forschungsgemeinschaft

a Grant for Joint Research Project of the Institute of Medical Science, University of Tokyo

Publisher

MDPI AG

Subject

Virology,Infectious Diseases

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