title: Inhibition of endoplasmic reticulum glucosidases is required for in vitro and in vivo dengue antiviral activity by the iminosugar UV-4.
abstract: The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease.
authors.affiliation: Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: warfieldk@ebsi.com.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: Emily.plummer@gmail.com.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Plummer
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: andrew.sayce@bioch.ox.ac.uk.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Sayce
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: dominic.alonzi@bioch.ox.ac.uk.
authors.forename: Dominic S
authors.initials: DS
authors.lastname: Alonzi
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: wtang@lji.org.
authors.forename: William
authors.initials: W
authors.lastname: Tang
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: beatrice.tyrrell@bioch.ox.ac.uk.
authors.forename: Beatrice E
authors.initials: BE
authors.lastname: Tyrrell
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: michelle.hill@bioch.ox.ac.uk.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Hill
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: alessandro.caputo@stx.ox.ac.uk.
authors.forename: Alessandro T
authors.initials: AT
authors.lastname: Caputo
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: sskillingbeck@ucdavis.edu.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Killingbeck
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: prbeatty@berkeley.edu.
authors.forename: P Robert
authors.initials: PR
authors.lastname: Beatty
authors.affiliation: Division of Infectious Diseases and Vaccinology, School of Public Health, University of California-Berkeley, Berkeley, CA, USA. Electronic address: eharris@berkeley.edu.
authors.forename: Eva
authors.initials: E
authors.lastname: Harris
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: r-iwaki@fujichemical.co.jp.
authors.forename: Ren
authors.initials: R
authors.lastname: Iwaki
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: s1160215@ems.u-toyama.ac.jp.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kinami
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: s1260204@ems.u-toyama.ac.jp.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ide
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: john.kiappes@bioch.ox.ac.uk.
authors.forename: J L
authors.initials: JL
authors.lastname: Kiappes
authors.affiliation: Department of Hospital Pharmacy, University of Toyama, Toyama, Japan. Electronic address: kato@med.u-toyama.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: mdsbuck@gmail.com.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Buck
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: kevindalesamuelking@gmail.com.
authors.forename: Kevin
authors.initials: K
authors.lastname: King
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: william.e.eddy@gmail.com.
authors.forename: William
authors.initials: W
authors.lastname: Eddy
authors.affiliation: Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: khlaliqm@ebsi.com.
authors.forename: Mansoora
authors.initials: M
authors.lastname: Khaliq
authors.affiliation: Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: sampatha1@ebsi.com.
authors.forename: Aruna
authors.initials: A
authors.lastname: Sampath
authors.affiliation: Emergent Virology LLC, Gaithersburg, MD 20879, USA. Electronic address: trestona@ebsi.com.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Treston
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: raymond.dwek@exeter.ox.ac.uk.
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Dwek
authors.affiliation: Integrated Biotherapeutics, Gaithersburg, MD 20878, USA. Electronic address: sven@integratedbiotherapeutics.com.
authors.forename: Sven G
authors.initials: SG
authors.lastname: Enterlein
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: joanna.miller@bioch.ox.ac.uk.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford, United Kingdom. Electronic address: nicole.zitzmann@bioch.ox.ac.uk.
authors.forename: Nicole
authors.initials: N
authors.lastname: Zitzmann
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: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Electronic address: sujan@lji.org.
authors.forename: Sujan
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authors.lastname: Shresta
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D019067:Antibody-Dependent Enhancement / Q000187:drug effects; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002986:Clinical Trials as Topic; D003716:Dengue Virus / Q000187:drug effects*; D004195:Disease Models, Animal; D015507:Drugs, Investigational; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D065089:Glycoside Hydrolase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009000:Monocytes / Q000821:virology; D017471:Receptors, Interferon / Q000172:deficiency; D065288:Serogroup; D019595:Severe Dengue / Q000188:drug therapy* / Q000821:virology; D014709:Vero Cells; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D015507:Drugs, Investigational; D065089:Glycoside Hydrolase Inhibitors; D017471:Receptors, Interferon; C120411:interferon receptor, type II; D017485:1-Deoxynojirimycin; C000604871:N-9-methoxynonyldeoxynojirimycin; D000520:alpha-Glucosidases
keywords: Antibody-dependent enhancement; Antiviral; Dengue; Glucosidase; Iminosugar; UV-4B