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

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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.

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Acknowledgments

We thank Dr. Yasumitsu Kondoh and Dr. Hiroyuki Osada, RIKEN Center for Sustainable Resource Science, for performing the chemical array screening, and Dr. T. Saito for supplying compounds from the RIKEN NPDepo chemical library. This research was supported by the Research Program on Emerging and Re-emerging Infectious Diseases of the Japan Agency for Medical Research and Development (AMED) under Grant Number JP18fk0108035, and by a RIKEN Program for Drug Discovery and Medical Technology Platforms.

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Authors and Affiliations

  1. Department of Virology I, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan

    Daiki Tohma, Shigeru Tajima, Fumihiro Kato, Chang-Kweng Lim & Masayuki Saijo

  2. Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, 2-2 Wakamatsucho, Shinjuku, Tokyo, 162-8480, Japan

    Daiki Tohma & Haruko Takeyama

  3. Nano Medical Engineering Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan

    Hirotaka Sato & Yoko Aida

  4. Virus Infectious Diseases Unit, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan

    Hirotaka Sato, Michinori Kakisaka & Yoko Aida

  5. Department of Microbiology, Kanagawa Prefectural Institute of Public Health, 1-3-1 Shimomachiya, Chigasaki, Kanagawa, 253-0087, Japan

    Takayuki Hishiki

  6. Department of Pathology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku, Tokyo, 162-8640, Japan

    Michiyo Kataoka

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  1. Daiki Tohma
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  2. Shigeru Tajima
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Correspondence to Shigeru Tajima.

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Handling Editor: Zhenhai Chen.

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Tohma, D., Tajima, S., Kato, F. et al. An estrogen antagonist, cyclofenil, has anti-dengue-virus activity. Arch Virol 164, 225–234 (2019). https://doi.org/10.1007/s00705-018-4079-0

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  • DOI: https://doi.org/10.1007/s00705-018-4079-0

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