An estrogen antagonist, cyclofenil, has anti-dengue-virus activity

Daiki Tohma, Shigeru Tajima, Fumihiro Kato, Hirotaka Sato, Michinori Kakisaka, Takayuki Hishiki, Michiyo Kataoka, Haruko Takeyama, Chang Kweng Lim, Yoko Aida, Masayuki Saijo

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Abstract

Dengue virus (DENV) infections are a major cause of morbidity and mortality in tropical and subtropical areas. Several compounds that act against DENV have been studied in clinical trials to date; however, there have been no compounds identified that are effective in reducing the severity of the clinical manifestations. To explore anti-DENV drugs, we examined small molecules that interact with DENV NS1 and inhibit DENV replication. Cyclofenil, which is a selective estrogen receptor modulator (SERM) and has been used clinically as an ovulation-inducing drug, showed an inhibitory effect on DENV replication in mammalian cells but not in mosquito cells. Other SERMs also inhibited DENV replication in mammalian cells, but cyclofenil showed the weakest cytotoxicity among these SERMs. Cyclofenil also inhibited the replication of Zika virus. A time-of-addition assay suggested that cyclofenil may interfere with two stages of the DENV life cycle: the translation-RNA synthesis and assembly-maturation stages. However, the level of intracellular infectious particles decreased more drastically after treatment with cyclofenil than the viral RNA level did, indicating that the assembly-maturation stage might be the main target of cyclofenil. In electron microscopy analysis, many aggregated particles were detected in DENV-infected cells in the presence of cyclofenil, supporting the possibility that cyclofenil impedes the process of assembly and maturation of DENV.

Original languageEnglish
Pages (from-to)225-234
Number of pages10
JournalArchives of Virology
Volume164
Issue number1
DOIs
Publication statusPublished - 2019 Jan 22

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ASJC Scopus subject areas

  • Virology

Cite this

Tohma, D., Tajima, S., Kato, F., Sato, H., Kakisaka, M., Hishiki, T., Kataoka, M., Takeyama, H., Lim, C. K., Aida, Y., & Saijo, M. (2019). An estrogen antagonist, cyclofenil, has anti-dengue-virus activity. Archives of Virology, 164(1), 225-234. https://doi.org/10.1007/s00705-018-4079-0