title: Clomiphene and Its Isomers Block Ebola Virus Particle Entry and Infection with Similar Potency: Potential Therapeutic Implications.
abstract: The 2014 outbreak of Ebola virus (EBOV) in Western Africa highlighted the need for anti-EBOV therapeutics. Clomiphene is a U.S. Food and Drug Administration (FDA)-approved drug that blocks EBOV entry and infection in cells and significantly protects EBOV-challenged mice. As provided, clomiphene is, approximately, a 60:40 mixture of two stereoisomers, enclomiphene and zuclomiphene. The pharmacokinetic properties of the two isomers vary, but both accumulate in the eye and male reproductive tract, tissues in which EBOV can persist. Here we compared the ability of clomiphene and its isomers to inhibit EBOV using viral-like particle (VLP) entry and transcription/replication-competent VLP (trVLP) assays. Clomiphene and its isomers inhibited the entry and infection of VLPs and trVLPs with similar potencies. This was demonstrated with VLPs bearing the glycoproteins from three filoviruses (EBOV Mayinga, EBOV Makona, and Marburg virus) and in two cell lines (293T/17 and Vero E6). Visual problems have been noted in EBOV survivors, and viral RNA has been isolated from semen up to nine months post-infection. Since the clomiphene isomers accumulate in these affected tissues, clomiphene or one of its isomers warrants consideration as an anti-EBOV agent, for example, to potentially help ameliorate symptoms in EBOV survivors.
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA. en2b@virginia.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Nelson
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA. abb9uu@virginia.edu.
authors.forename: Alyson B
authors.initials: AB
authors.lastname: Barnes
authors.affiliation: Repros Therapeutics, Inc., The Woodlands, TX 77380, USA. rwiehle@reprosrx.com.
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Wiehle
authors.affiliation: Repros Therapeutics, Inc., The Woodlands, TX 77380, USA. GFontenot@reprosrx.com.
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Fontenot
authors.affiliation: Laboratory of Virology, Division of Intramural Research, National Institutes of Health, Hamilton, MT 59840, USA. thomas.hoenen@fli.bund.de.|Friedrich-Loeffler-Institut, D-17493, Greifswald-Insel Riems, Germany. thomas.hoenen@fli.bund.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hoenen
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA. jw7g@virginia.edu.
authors.forename: Judith M
authors.initials: JM
authors.lastname: White
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002996:Clomiphene / Q000494:pharmacology*; D029043:Ebolavirus / Q000187:drug effects* / Q000502:physiology*; D019142:Hemorrhagic Fever, Ebola / Q000188:drug therapy; D006801:Humans; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D053586:Virus Internalization / Q000187:drug effects*; D064696:Zuclomiphene / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D020845:Selective Estrogen Receptor Modulators; D002996:Clomiphene; D064696:Zuclomiphene
keywords: Ebola; Ebola Virus disease; Ebola virus survivors; anti-viral; enclomiphene; filovirus; zuclomiphene