title: Assessment of the potential for host-targeted iminosugars UV-4 and UV-5 activity against filovirus infections in vitro and in vivo.
abstract: Iminosugars are host-directed antivirals with broad-spectrum activity. The iminosugar, N-butyl-deoxynojirimycin (NB-DNJ or Miglustat®), is used in humans for treatment of Gaucher's disease and has mild antiviral properties. More potent analogs of NB-DNJ have been generated and have demonstrated activity against a variety of viruses including flaviviruses, influenza, herpesviruses and filoviruses. In the current study, a panel of analogs based on NB-DNJ was analyzed for activity against Ebola (EBOV) and Marburg viruses (MARV). The antiviral activity of NB-DNJ (UV-1), UV-2, UV-3, UV-4 and UV-5 against both EBOV and MARV was demonstrated in Vero cells. Subsequent studies to examine the activity of UV-4 and UV-5 using rodent models of EBOV and MARV were performed. In vivo efficacy studies provided inconsistent data following treatment with iminosugars using filovirus mouse models. A tolerability study in nonhuman primates demonstrated that UV-4 could be administered at much higher dose levels than rodents. Since UV-4 was active in vitro, had been demonstrated to be active against influenza and dengue in vivo, and was being tested in a Phase 1 clinical trial, a small proof-of-concept nonhuman primate trial was performed to determine whether this antiviral candidate could provide clinical benefit to EBOV-infected individuals. Administration of UV-4B did not provide a clinical or survival benefit to macaques infected with EBOV-Makona; however, dosing of animals was not optimal in this study. Efficacy may be improved by thrice daily dosing (e.g. by nasogastric tube feeding) to match the efficacious dosing regimens demonstrated against dengue and influenza viruses.
authors.affiliation: Emergent BioSolutions, Gaithersburg, MD 20879, USA. Electronic address: warfieldk@ebsi.com.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.affiliation: United States Army Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA. Electronic address: travis.k.warren.ctr@mail.mil.
authors.forename: Travis K
authors.initials: TK
authors.lastname: Warren
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada. Electronic address: Xiangguo.qiu@phac-aspc.gc.ca.
authors.forename: Xiangguo
authors.initials: X
authors.lastname: Qiu
authors.affiliation: United States Army Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA. Electronic address: jay.b.wells.ctr@mail.mil.
authors.forename: Jay
authors.initials: J
authors.lastname: Wells
authors.affiliation: University of Texas Medical Branch, Galveston National Laboratory, Galveston, TX 77550, USA. Electronic address: cmire@utmb.edu.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Mire
authors.affiliation: University of Texas Medical Branch, Galveston National Laboratory, Galveston, TX 77550, USA. Electronic address: jbgeisbe@utmb.edu.
authors.forename: Joan B
authors.initials: JB
authors.lastname: Geisbert
authors.affiliation: United States Army Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA. Electronic address: Kelly.s.stuthman.ctr@mail.mil.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Stuthman
authors.affiliation: United States Army Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA. Electronic address: nicole.l.lackemeyer.ctr@mail.mil.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Garza
authors.affiliation: United States Army Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA. Electronic address: sean.a.vantongeren.ctr@mail.mil.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Van Tongeren
authors.affiliation: United States Army Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA. Electronic address: amy.c.shurtleff.ctr@mail.mil.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Shurtleff
authors.affiliation: University of Texas Medical Branch, Galveston National Laboratory, Galveston, TX 77550, USA. Electronic address: knagans@utmb.edu.
authors.forename: Krystle N
authors.initials: KN
authors.lastname: Agans
authors.affiliation: Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada; CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. Electronic address: garyckwong@hotmail.com.
authors.forename: Gary
authors.initials: G
authors.lastname: Wong
authors.affiliation: Unither Virology LLC, Silver Spring, MD 20910, USA; Division of Infectious Diseases, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA. Electronic address: mvcallahan@mgh.harvard.edu.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Callahan
authors.affiliation: University of Texas Medical Branch, Galveston National Laboratory, Galveston, TX 77550, USA. Electronic address: twgeisbe@utmb.edu.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Geisbert
authors.affiliation: Unither Virology LLC, Silver Spring, MD 20910, USA. Electronic address: brennan.klose@abviro.com.
authors.forename: Brennan
authors.initials: B
authors.lastname: Klose
authors.affiliation: Unither Virology LLC, Silver Spring, MD 20910, USA. Electronic address: urban_ramstedt@yahoo.com.
authors.forename: Urban
authors.initials: U
authors.lastname: Ramstedt
authors.affiliation: Emergent BioSolutions, Gaithersburg, MD 20879, USA. Electronic address: trestona@ebsi.com.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Treston
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000819:agonists / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D029043:Ebolavirus / Q000187:drug effects*; D050111:Imino Sugars / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D008251:Macaca; D029024:Marburgvirus / Q000187:drug effects*; D051379:Mice; D023421:Models, Animal; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D050111:Imino Sugars; D017485:1-Deoxynojirimycin; C000604871:N-9-methoxynonyldeoxynojirimycin; C059896:miglustat
keywords: Antiviral; Ebola virus; Glucosidase; Iminosugar; Marburg virus; UV-4B