An estrogen antagonist, cyclofenil, has anti-dengue-virus activity
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.
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.
This article contains no studies with human participants or animals performed by the authors.
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