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.
Highlights
IntroductionViruses belonging to the Arenaviridae family that infect mammals (mammarenaviruses) are serologically and geographically classified into the Old World and New World mammarenaviruses
Vero cells grown in 96-well plates were treated with each of the respective compounds at a concentration of 10 μM and were infected with vesicular stomatitis virus (VSV)-LASV glycoprotein (LASVGP) at an multiplicity of infection (MOI) of 0.01
Since CP100356 showed antiviral activity against Lassa virus (LASV) and lymphocytic choriomeningitis virus (LCMV), we further investigated whether it inhibits the entry of other mammarenaviruses
Summary
Viruses belonging to the Arenaviridae family that infect mammals (mammarenaviruses) are serologically and geographically classified into the Old World and New World mammarenaviruses. The Old World serogroup includes Lassa virus (LASV), the causative agent of Lassa fever in West Africa, which in its severe forms results in hemorrhagic fever and lymphocytic choriomeningitis virus (LCMV), which in severe cases causes neurological disease in humans [1,2]. New World viruses, i.e., Junín, Machupo, Guanarito, Sabiá, and Chapare viruses, cause hemorrhagic fever and neurological disease in humans in South. These highly pathogenic mammarenaviruses including LASV are classified as Category A bioterrorism agents and must be handled in a biosafety level-4 (BSL-4) facility
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