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Archives of Virology

, Volume 164, Issue 1, pp 225–234 | Cite as

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

  • Daiki Tohma
  • Shigeru TajimaEmail author
  • Fumihiro Kato
  • Hirotaka Sato
  • Michinori Kakisaka
  • Takayuki Hishiki
  • Michiyo Kataoka
  • Haruko Takeyama
  • Chang-Kweng Lim
  • Yoko Aida
  • Masayuki Saijo
Original Article

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.

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest associated with this article.

Ethical approval

This article contains no studies with human participants or animals performed by the authors.

Supplementary material

705_2018_4079_MOESM1_ESM.pptx (644 kb)
Supplementary material 1 (PPTX 644 kb)

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Daiki Tohma
    • 1
    • 2
  • Shigeru Tajima
    • 1
    Email author
  • Fumihiro Kato
    • 1
  • Hirotaka Sato
    • 3
    • 4
  • Michinori Kakisaka
    • 4
  • Takayuki Hishiki
    • 5
  • Michiyo Kataoka
    • 6
  • Haruko Takeyama
    • 2
  • Chang-Kweng Lim
    • 1
  • Yoko Aida
    • 3
    • 4
  • Masayuki Saijo
    • 1
  1. 1.Department of Virology INational Institute of Infectious DiseasesShinjukuJapan
  2. 2.Department of Life Science and Medical Bioscience, School of Advanced Science and EngineeringWaseda UniversityShinjukuJapan
  3. 3.Nano Medical Engineering LaboratoryRIKEN Cluster for Pioneering ResearchWakoJapan
  4. 4.Virus Infectious Diseases UnitRIKENWakoJapan
  5. 5.Department of MicrobiologyKanagawa Prefectural Institute of Public HealthChigasakiJapan
  6. 6.Department of PathologyNational Institute of Infectious DiseasesShinjukuJapan

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