Hexestrol, an estrogen receptor agonist, inhibits Lassa virus entry.

Autor: Zhang Z; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan., Takenaga T; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan., Fehling SK; Institute of Virology, Phillips University Marburg, Marburg, Germany., Igarashi M; Division of Global Epidemiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan.; International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo, Japan., Hirokawa T; Transborder Medical Research Center, University of Tsukuba, Tsukuba, Ibaraki, Japan.; Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan., Muramoto Y; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan., Yamauchi K; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan., Onishi C; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan., Nakano M; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan., Urata S; National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, Nagasaki, Japan., Groseth A; Laboratory for Arenavirus Biology, Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany., Strecker T; Institute of Virology, Phillips University Marburg, Marburg, Germany., Noda T; Laboratory of Ultrastructural Virology, Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.; Laboratory of Ultrastructural Virology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.; CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
Jazyk: angličtina
Zdroj: Journal of virology [J Virol] 2024 Jul 23; Vol. 98 (7), pp. e0071424. Date of Electronic Publication: 2024 May 29.
DOI: 10.1128/jvi.00714-24
Abstrakt: Lassa virus (LASV) is the causative agent of human Lassa fever which in severe cases manifests as hemorrhagic fever leading to thousands of deaths annually. However, no approved vaccines or antiviral drugs are currently available. Recently, we screened approximately 2,500 compounds using a recombinant vesicular stomatitis virus (VSV) expressing LASV glycoprotein GP (VSV-LASVGP) and identified a P-glycoprotein inhibitor as a potential LASV entry inhibitor. Here, we show that another identified candidate, hexestrol (HES), an estrogen receptor agonist, is also a LASV entry inhibitor. HES inhibited VSV-LASVGP replication with a 50% inhibitory concentration (IC 50 ) of 0.63 µM. Importantly, HES also inhibited authentic LASV replication with IC 50 values of 0.31 µM-0.61 µM. Time-of-addition and cell-based membrane fusion assays suggested that HES inhibits the membrane fusion step during virus entry. Alternative estrogen receptor agonists did not inhibit VSV-LASVGP replication, suggesting that the estrogen receptor itself is unlikely to be involved in the antiviral activity of HES. Generation of a HES-resistant mutant revealed that the phenylalanine at amino acid position 446 (F446) of LASVGP, which is located in the transmembrane region, conferred resistance to HES. Although mutation of F446 enhanced the membrane fusion activity of LASVGP, it exhibited reduced VSV-LASVGP replication, most likely due to the instability of the pre-fusion state of LASVGP. Collectively, our results demonstrated that HES is a promising anti-LASV drug that acts by inhibiting the membrane fusion step of LASV entry. This study also highlights the importance of the LASVGP transmembrane region as a target for anti-LASV drugs.IMPORTANCELassa virus (LASV), the causative agent of Lassa fever, is the most devastating mammarenavirus with respect to its impact on public health in West Africa. However, no approved antiviral drugs or vaccines are currently available. Here, we identified hexestrol (HES), an estrogen receptor agonist, as the potential antiviral candidate drug. We showed that the estrogen receptor itself is not involved in the antiviral activity. HES directly bound to LASVGP and blocked membrane fusion, thereby inhibiting LASV infection. Through the generation of a HES-resistant virus, we found that phenylalanine at position 446 (F446) within the LASVGP transmembrane region plays a crucial role in the antiviral activity of HES. The mutation at F446 caused reduced virus replication, likely due to the instability of the pre-fusion state of LASVGP. These findings highlight the potential of HES as a promising candidate for the development of antiviral compounds targeting LASV.
Competing Interests: The authors declare no conflict of interest.
Databáze: MEDLINE
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